Case ReportNeurological Manifestations of X-Linked IchthyosisCase Report and Review of the Literature

William S Baek1 and Umut Aypar2

1Parkside Medical Group 1310 San Bernardino Rd Suite 102 Upland CA 91786 USA2Division of Laboratory Genetics Department of Laboratory Medicine amp Pathology Mayo Clinic 200 First Street SWRochester MN 55905 USA

Correspondence should be addressed to William S Baek william s baekhotmailcom

Received 8 February 2017 Revised 2 May 2017 Accepted 12 July 2017 Published 13 August 2017

Academic Editor Balraj Mittal

Copyright copy 2017 William S Baek and Umut Aypar This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

A 5-year-old boy presented with mild autism and attention-deficit hyperactivity disorder (ADHD) Chromosomal microarraydemonstrated a 17Mb deletion at Xp2231 which was consistent with X-linked ichthyosis (XLI) Further exam revealed dry scalyskin on his abdomen and pretibial areas Patients withmutations involving solely the STS gene or the recurrent sim2Mb deletionmaypresent with ADHD whereas those with larger deletions including the NLGN4 gene can present with both ADHD and autismHowever our patient presented with mild autism in addition to ADHD despite having only the recurrent deletion without loss ofNLGN4 Such neurological manifestations of XLI warrant attention as practical targets of clinical management

1 Introduction

X-linked ichthyosis (XLI) is an X-linked recessive disorderwith a prevalence of approximately 1 4000 demonstratingdry scaly skin due to a deficiency of the enzyme steroidsulfatase [1] While patients with mutations involving solelythe STS gene or the recurrent sim2Mb deletion can presentwith attention-deficit hyperactivity disorder (ADHD) thosewith larger deletions including neighboring genes such asneuroligin 4 (NLGN4) may present with autism in additionto ADHD [2 3]

We present a case of XLI with ADHD and mild autismdue to a recurrent sim2Mb deletion which spared the NLGN4gene

2 Case Presentation

A 5-year-old boy (43 inches 50th percentile and 42 lbs 50thpercentile) presented to Parkside Medical Group (UplandCA) for a neurological evaluation His mother rememberedbeing told that he might have intellectual disability basedon blood tests and an amniocentesis however these test

results were not available Otherwise the pregnancy historyand delivery were normal He weighed 6 lbs 10 oz (20thpercentile) at birth walked at 14 months and said ldquomamardquoand ldquopapardquo at 8-9 months During early childhood he did notwant to be around other children He adhered to routinesfor example when his father would change his favorite TVchannel he would become very angry He spoke Spanish andsome English He attended special education at a preschoollevel and he could count up to 100 However he could notfocus in school He was diagnosed with ADHD and mildautism based on the DSM V criteria by a child psychologistsix months prior to the neurology visit He was startedon amphetamine-dextroamphetamine ER 10mg daily whichimproved his behavior both at home and at school He startedparticipatingmore in group activities On exam hewas foundto have a high anterior hairline a triangular face a short chinwidely spaced eyes prominent nasal bridge and conical teeth(Figure 1) There were no corneal opacities or preauricularscales He was able to answer questions about his name ageand what he liked but there was a lack of reciprocity andeye contact There were no tics However he was fidgetycould not wait his turn was wandering about was talking

HindawiCase Reports in GeneticsVolume 2017 Article ID 9086408 5 pageshttpsdoiorg10115520179086408

2 Case Reports in Genetics

(a) (b)

(c)Figure 1 (a) Facial features include the high anterior hairline a triangular face a short chin widely spaced eyes and prominent nasal bridgeThe dry scaly skin was observed in (b) the pretibial areas and (c) the abdomen

excessively in Spanish and was interrupting his parents attimes Therefore his Adderall XR was increased to 20mgdaily but he became weepy and emotional hence the dosewas lowered back to 10mg daily but 7 months later the dosehad to be increased back to 15mg daily due to his persistentsymptoms of ADHD He was also treated for insomnia withguanfacine 05mg at night Of note he had a history of

asthma and was being treated with budesonide 05mg2mLsuspension and montelukast 4mg daily Family history wasunremarkable He has an 11-year-old healthy sisterThere wasno history of consanguinity His EKG was normal There wasno history of seizures EEG was not performed due to lack ofcooperation His lab results were all normal (cholesterol TGHDL LDL FSH LH TSH ACTH vitamin A free retinol

Case Reports in Genetics 3

(a)

(b)

Copy number state (segments)

Smooth signal

Allele dierence

0 5000 5500 6000 6500 7000 7500 8000 8500 9000 9500

(kb)

p2231p2232

ＦＩＡ 2 ratio

Figure 2 (a) Affymetrix CytoScan chromosomal microarray analysis detected a 17Mb deletion at Xp2231 (6458939ndash8135644 genomebuild hg 19) in our male patient (b) UCSC genome browser image showing the Xp2231 deletion The deleted interval contains six knowngenes (PUDP STS MIR4767 VCX PNPLA4 and MIR651)

and plac Lp PLA2) except for human growth hormone whichwas elevated (16 ngml normal range 001ndash097 ngml) Hetested negative for fragile X syndrome with 29 CGG repeatsChromosomal microarray (CMA) performed at the MayoClinic (Rochester MN) demonstrated a 17Mb deletion atXp2231 (Figure 2) which included 6 genes STS pseudouri-dine 51015840-phosphatase (PUDP) microRNA 4767 (MIR4767)variable charge X-linked (VCX) patatin-like phospholi-pase domain containing 4 (PNPLA4) and microRNA 651(MIR651) which was consistent with the diagnosis of XLI [45] CMAwas performed using both copy number and single-nucleotide polymorphism (SNP) probes on a whole genomearray (CytoScan HD platform) (Affymetrix) The genome-wide functional resolution of this array is approximately 30 kbfor deletions and 60 kb for duplications The presence of dryscaly skin on his abdomen and pretibial areas (Figure 1) wasconfirmed after receiving the results of the array There wereno signs of cryptorchidismThe patientrsquos mother could not betested due to lack of insurance coverage

3 Discussion

Here we present a case of XLI with 17Mb deletion at Xp2231which included the STS gene as well as 5 other genes In

addition to the classic features of XLI of dry scaly skin(Figure 1) he also presented with ADHD and mild autismDuring the pregnancy his mother recalls some blood teststhat are not available but presumably they showed low orundetectable serum levels of unconjugated estriol which canbe seen in XLI

XLI was first described by Sedgwick in 1863 [6] XLI isX-linked recessive therefore it occurs almost exclusively inboys with a prevalence of approximately 1 4000 [1] It isdue to a lack of the enzyme steroid sulfatase as a result ofmutations or deletions of the STS gene which is located in thedistal part of the short arm of the X chromosome (Xp2231)[7] XLI presents with dry scaly skin (ichthyosis) skinlesions corneal opacities and cryptorchidism [1] Patientswith mutations involving only the STS gene or the recurrentsim2Mb deletionmay present with ADHD whereas those withlarger deletions (involving not only STS or genes in therecurrent sim2Mb deletion but also other neighboring genessuch as NLGN4) may present with ADHD andor autism[2 3] Since patients with only STS mutations or recurrent sim2Mb deletions have not demonstrated any autistic features itwas considered that the loss of one ormore of the neighboringgenes within the larger deletions is contributing to autism [3]

4 Case Reports in Genetics

In our patient chromosomal microarray revealed therecurrent sim2Mb deletion which included the followinggenes STS PUDP MIR4767 VCX PNPLA4 and MIR651The significance of PUDPMIR4767 andMIR651 is uncertainas there is not much known about the biological role ofthese genes PUDP encodes a member of the haloaciddehalogenase-like (HAD) hydrolase superfamily howeverthe encoded protein has no known biological function [8]There is no information available on MIR4767 and MIR651with regard to their targets [8] VCX (variable charge X-linked) gene belongs to the VCXY gene family all of whichare expressed exclusively in male germ cells While it isconsidered that the VCXY genes encode for small and highlycharged nuclear proteins their function is yet to be elucidated[8] Although there have been conflicting reports on the asso-ciation between VCX3A and an abnormal neurocognitivephenotype no such correlation exists with the gene deletedin our patient (VCX) or with other gene family members(VCX2 VCX3B) [9 10] PNPLA4 encodes a member ofthe patatin-like family of phospholipases which has bothtriacylglycerol lipase and transacylase activities PNPLA4may be involved in adipocyte triglyceride homeostasis [11]It has also been implicated as a causal gene for autism [7]STS belongs to the sulfatase family and hydrolyzes several3-beta-hydroxysteroid sulfates converting specifically thesulfated form of dehydroepiandrosterone otherwise knownas DHEA-S to DHEA [8] These are both neurosteroidswhich exhibit effects on neurophysiological and behavioralprocesses Lower levels of DHEA in the blood have beenassociated with ADHD phenotype [12] This could explainthe link between loss of STS gene function and ADHD in XLIpatients In addition animal studies suggest that the STS genemay be implicated in processes involving attention [13]

Kent et al [2] reported that out of 25 male patientswith either STS point mutations or recurrent sim2Mb dele-tions 40 fulfilled DSM-IV criteria for ADHD (comparedto population rate 36) 80 of which were inattentivesubtype Five had fulfilled criteria for an autistic spectrumdisorder or related languagecommunication disorders andall of them had unusually large deletions of the STS gene withloss of the NLGN4 gene Males with solely STS mutationsor recurrent sim2Mb deletions did not demonstrate autisticdifficulties Therefore NLGN4 was suggested as a causativegene for autism in XLI patients with larger deletions

In our patient however the recurrent sim2Mb dele-tion (including STS PUDP MIR4767 VCX PNPLA4 andMIR651 but sparing NLGN4) was sufficient to cause bothmild autism and ADHD

Our case report highlights the importance of a neu-rological evaluation in XLI due to the association withADHDand autism especially thosewith the recurrentsim2Mbdeletions and those with larger deletions including NLGN4In addition we suggest that clinical cytogenetics laboratorieswhich report these deletions should indicate the risk forthe neurological manifestations in their interpretation inaddition to the skinmanifestations and other clinical featuresIn conclusion we hope to bring awareness of the neurologicalmanifestations of XLI among neurologists and geneticists(both laboratory and clinical)

4 Materials and Methods

Genomic DNA extraction and chromosomal microarrayanalysis were performed with the previously describedmeth-ods [14] Informed consent was obtained from themother forthe photographs

Disclosure

No statistical analysis was required

Conflicts of Interest

The authors declare that they have no conflicts of interest

References

[1] H Traupe J Fischer and V Oji ldquoNonsyndromic types ofichthyosesmdashan updaterdquo Journal of the German Society of Der-matology vol 12 no 2 pp 109ndash121 2014

[2] L Kent J Emerton V Bhadravathi et al ldquoX-linked ichthyosis(steroid sulfatase deficiency) is associated with increased riskof attention deficit hyperactivity disorder autism and socialcommunication deficitsrdquo Journal of Medical Genetics vol 45no 8 pp 519ndash524 2008

[3] K J Brookes Z Hawi A Kirley E Barry M Gill and L KentldquoAssociation of the steroid sulfatase (STS) gene with attentiondeficit hyperactivity disorderrdquo American Journal of MedicalGenetics Part B Neuropsychiatric Genetics vol 147 no 8 pp1531ndash1535 2008

[4] A Ballabio M Zollo R Carrozzo et al ldquoDeletion of the distalshort arm of the X chromosome (Xp) in a patient with shortstature chondrodysplasia punctata and X-linked ichthyosisdue to steroid sulfatase deficiencyrdquoAmerican Journal of MedicalGenetics vol 41 no 2 pp 184ndash187 1991

[5] R E Schnur B J Trask G Van den Engh et al ldquoAn Xp22microdeletion associated with ocular albinism and ichthyosisApproximation of breakpoints and estimation of deletion sizeby using cloned DNA probes and flow cytometryrdquo AmericanJournal of Human Genetics vol 45 no 5 pp 706ndash720 1989

[6] W Sedgwick ldquoOn the Influence of Sex in Hereditary DiseaserdquoTheBritish Journal of Psychiatry vol 9 no 47 pp 405ndash410 1863

[7] M Carmen Carrascosa-Romero J Suela B Alfaro-Ponce andA J Cepillo-Boluda ldquoX-chromosome-linked ichthyosis associ-ated to epilepsy hyperactivity autism and mental retardationdue to the Xp2231 microdeletionrdquo Revista de Neurologia vol54 no 4 pp 241ndash248 2012

[8] httpswwwncbinlmnihgovrefseq[9] H Ben Khelifa N Soyah I Ben-Abdallah-Bouhjar et al

ldquoXp223 interstitial deletion A recognizable chromosomalabnormality encompassing VCX3A and STS genes in a patientwith X-linked ichthyosis andmental retardationrdquoGene vol 527no 2 pp 578ndash583 2013

[10] S ACuevas-Covarrubias andLMGonzalez-Huerta ldquoAnalysisof the VCX3A VCX2 and VCX3B genes shows that VCX3Agene deletion is not sufficient to result in mental retardation inX-linked ichthyosisrdquoBritish Journal ofDermatology vol 158 no3 pp 483ndash486 2008

[11] P A Wilson S D Gardner N M Lambie S A Commansand D J Crowther ldquoCharacterization of the human patatin-like

Case Reports in Genetics 3

(a)

(b)

Copy number state (segments)

Smooth signal

Allele dierence

0 5000 5500 6000 6500 7000 7500 8000 8500 9000 9500

(kb)

p2231p2232

ＦＩＡ 2 ratio

Figure 2 (a) Affymetrix CytoScan chromosomal microarray analysis detected a 17Mb deletion at Xp2231 (6458939ndash8135644 genomebuild hg 19) in our male patient (b) UCSC genome browser image showing the Xp2231 deletion The deleted interval contains six knowngenes (PUDP STS MIR4767 VCX PNPLA4 and MIR651)

and plac Lp PLA2) except for human growth hormone whichwas elevated (16 ngml normal range 001ndash097 ngml) Hetested negative for fragile X syndrome with 29 CGG repeatsChromosomal microarray (CMA) performed at the MayoClinic (Rochester MN) demonstrated a 17Mb deletion atXp2231 (Figure 2) which included 6 genes STS pseudouri-dine 51015840-phosphatase (PUDP) microRNA 4767 (MIR4767)variable charge X-linked (VCX) patatin-like phospholi-pase domain containing 4 (PNPLA4) and microRNA 651(MIR651) which was consistent with the diagnosis of XLI [45] CMAwas performed using both copy number and single-nucleotide polymorphism (SNP) probes on a whole genomearray (CytoScan HD platform) (Affymetrix) The genome-wide functional resolution of this array is approximately 30 kbfor deletions and 60 kb for duplications The presence of dryscaly skin on his abdomen and pretibial areas (Figure 1) wasconfirmed after receiving the results of the array There wereno signs of cryptorchidismThe patientrsquos mother could not betested due to lack of insurance coverage

3 Discussion

Here we present a case of XLI with 17Mb deletion at Xp2231which included the STS gene as well as 5 other genes In

addition to the classic features of XLI of dry scaly skin(Figure 1) he also presented with ADHD and mild autismDuring the pregnancy his mother recalls some blood teststhat are not available but presumably they showed low orundetectable serum levels of unconjugated estriol which canbe seen in XLI

XLI was first described by Sedgwick in 1863 [6] XLI isX-linked recessive therefore it occurs almost exclusively inboys with a prevalence of approximately 1 4000 [1] It isdue to a lack of the enzyme steroid sulfatase as a result ofmutations or deletions of the STS gene which is located in thedistal part of the short arm of the X chromosome (Xp2231)[7] XLI presents with dry scaly skin (ichthyosis) skinlesions corneal opacities and cryptorchidism [1] Patientswith mutations involving only the STS gene or the recurrentsim2Mb deletionmay present with ADHD whereas those withlarger deletions (involving not only STS or genes in therecurrent sim2Mb deletion but also other neighboring genessuch as NLGN4) may present with ADHD andor autism[2 3] Since patients with only STS mutations or recurrent sim2Mb deletions have not demonstrated any autistic features itwas considered that the loss of one ormore of the neighboringgenes within the larger deletions is contributing to autism [3]

4 Case Reports in Genetics

In our patient chromosomal microarray revealed therecurrent sim2Mb deletion which included the followinggenes STS PUDP MIR4767 VCX PNPLA4 and MIR651The significance of PUDPMIR4767 andMIR651 is uncertainas there is not much known about the biological role ofthese genes PUDP encodes a member of the haloaciddehalogenase-like (HAD) hydrolase superfamily howeverthe encoded protein has no known biological function [8]There is no information available on MIR4767 and MIR651with regard to their targets [8] VCX (variable charge X-linked) gene belongs to the VCXY gene family all of whichare expressed exclusively in male germ cells While it isconsidered that the VCXY genes encode for small and highlycharged nuclear proteins their function is yet to be elucidated[8] Although there have been conflicting reports on the asso-ciation between VCX3A and an abnormal neurocognitivephenotype no such correlation exists with the gene deletedin our patient (VCX) or with other gene family members(VCX2 VCX3B) [9 10] PNPLA4 encodes a member ofthe patatin-like family of phospholipases which has bothtriacylglycerol lipase and transacylase activities PNPLA4may be involved in adipocyte triglyceride homeostasis [11]It has also been implicated as a causal gene for autism [7]STS belongs to the sulfatase family and hydrolyzes several3-beta-hydroxysteroid sulfates converting specifically thesulfated form of dehydroepiandrosterone otherwise knownas DHEA-S to DHEA [8] These are both neurosteroidswhich exhibit effects on neurophysiological and behavioralprocesses Lower levels of DHEA in the blood have beenassociated with ADHD phenotype [12] This could explainthe link between loss of STS gene function and ADHD in XLIpatients In addition animal studies suggest that the STS genemay be implicated in processes involving attention [13]

Kent et al [2] reported that out of 25 male patientswith either STS point mutations or recurrent sim2Mb dele-tions 40 fulfilled DSM-IV criteria for ADHD (comparedto population rate 36) 80 of which were inattentivesubtype Five had fulfilled criteria for an autistic spectrumdisorder or related languagecommunication disorders andall of them had unusually large deletions of the STS gene withloss of the NLGN4 gene Males with solely STS mutationsor recurrent sim2Mb deletions did not demonstrate autisticdifficulties Therefore NLGN4 was suggested as a causativegene for autism in XLI patients with larger deletions

In our patient however the recurrent sim2Mb dele-tion (including STS PUDP MIR4767 VCX PNPLA4 andMIR651 but sparing NLGN4) was sufficient to cause bothmild autism and ADHD

Our case report highlights the importance of a neu-rological evaluation in XLI due to the association withADHDand autism especially thosewith the recurrentsim2Mbdeletions and those with larger deletions including NLGN4In addition we suggest that clinical cytogenetics laboratorieswhich report these deletions should indicate the risk forthe neurological manifestations in their interpretation inaddition to the skinmanifestations and other clinical featuresIn conclusion we hope to bring awareness of the neurologicalmanifestations of XLI among neurologists and geneticists(both laboratory and clinical)

4 Materials and Methods

Genomic DNA extraction and chromosomal microarrayanalysis were performed with the previously describedmeth-ods [14] Informed consent was obtained from themother forthe photographs

Disclosure

No statistical analysis was required

Conflicts of Interest

The authors declare that they have no conflicts of interest

References

[1] H Traupe J Fischer and V Oji ldquoNonsyndromic types ofichthyosesmdashan updaterdquo Journal of the German Society of Der-matology vol 12 no 2 pp 109ndash121 2014

[2] L Kent J Emerton V Bhadravathi et al ldquoX-linked ichthyosis(steroid sulfatase deficiency) is associated with increased riskof attention deficit hyperactivity disorder autism and socialcommunication deficitsrdquo Journal of Medical Genetics vol 45no 8 pp 519ndash524 2008

[3] K J Brookes Z Hawi A Kirley E Barry M Gill and L KentldquoAssociation of the steroid sulfatase (STS) gene with attentiondeficit hyperactivity disorderrdquo American Journal of MedicalGenetics Part B Neuropsychiatric Genetics vol 147 no 8 pp1531ndash1535 2008

[4] A Ballabio M Zollo R Carrozzo et al ldquoDeletion of the distalshort arm of the X chromosome (Xp) in a patient with shortstature chondrodysplasia punctata and X-linked ichthyosisdue to steroid sulfatase deficiencyrdquoAmerican Journal of MedicalGenetics vol 41 no 2 pp 184ndash187 1991

[5] R E Schnur B J Trask G Van den Engh et al ldquoAn Xp22microdeletion associated with ocular albinism and ichthyosisApproximation of breakpoints and estimation of deletion sizeby using cloned DNA probes and flow cytometryrdquo AmericanJournal of Human Genetics vol 45 no 5 pp 706ndash720 1989

[6] W Sedgwick ldquoOn the Influence of Sex in Hereditary DiseaserdquoTheBritish Journal of Psychiatry vol 9 no 47 pp 405ndash410 1863

[7] M Carmen Carrascosa-Romero J Suela B Alfaro-Ponce andA J Cepillo-Boluda ldquoX-chromosome-linked ichthyosis associ-ated to epilepsy hyperactivity autism and mental retardationdue to the Xp2231 microdeletionrdquo Revista de Neurologia vol54 no 4 pp 241ndash248 2012

[8] httpswwwncbinlmnihgovrefseq[9] H Ben Khelifa N Soyah I Ben-Abdallah-Bouhjar et al

ldquoXp223 interstitial deletion A recognizable chromosomalabnormality encompassing VCX3A and STS genes in a patientwith X-linked ichthyosis andmental retardationrdquoGene vol 527no 2 pp 578ndash583 2013

[10] S ACuevas-Covarrubias andLMGonzalez-Huerta ldquoAnalysisof the VCX3A VCX2 and VCX3B genes shows that VCX3Agene deletion is not sufficient to result in mental retardation inX-linked ichthyosisrdquoBritish Journal ofDermatology vol 158 no3 pp 483ndash486 2008

[11] P A Wilson S D Gardner N M Lambie S A Commansand D J Crowther ldquoCharacterization of the human patatin-like

4 Case Reports in Genetics

In our patient chromosomal microarray revealed therecurrent sim2Mb deletion which included the followinggenes STS PUDP MIR4767 VCX PNPLA4 and MIR651The significance of PUDPMIR4767 andMIR651 is uncertainas there is not much known about the biological role ofthese genes PUDP encodes a member of the haloaciddehalogenase-like (HAD) hydrolase superfamily howeverthe encoded protein has no known biological function [8]There is no information available on MIR4767 and MIR651with regard to their targets [8] VCX (variable charge X-linked) gene belongs to the VCXY gene family all of whichare expressed exclusively in male germ cells While it isconsidered that the VCXY genes encode for small and highlycharged nuclear proteins their function is yet to be elucidated[8] Although there have been conflicting reports on the asso-ciation between VCX3A and an abnormal neurocognitivephenotype no such correlation exists with the gene deletedin our patient (VCX) or with other gene family members(VCX2 VCX3B) [9 10] PNPLA4 encodes a member ofthe patatin-like family of phospholipases which has bothtriacylglycerol lipase and transacylase activities PNPLA4may be involved in adipocyte triglyceride homeostasis [11]It has also been implicated as a causal gene for autism [7]STS belongs to the sulfatase family and hydrolyzes several3-beta-hydroxysteroid sulfates converting specifically thesulfated form of dehydroepiandrosterone otherwise knownas DHEA-S to DHEA [8] These are both neurosteroidswhich exhibit effects on neurophysiological and behavioralprocesses Lower levels of DHEA in the blood have beenassociated with ADHD phenotype [12] This could explainthe link between loss of STS gene function and ADHD in XLIpatients In addition animal studies suggest that the STS genemay be implicated in processes involving attention [13]

Kent et al [2] reported that out of 25 male patientswith either STS point mutations or recurrent sim2Mb dele-tions 40 fulfilled DSM-IV criteria for ADHD (comparedto population rate 36) 80 of which were inattentivesubtype Five had fulfilled criteria for an autistic spectrumdisorder or related languagecommunication disorders andall of them had unusually large deletions of the STS gene withloss of the NLGN4 gene Males with solely STS mutationsor recurrent sim2Mb deletions did not demonstrate autisticdifficulties Therefore NLGN4 was suggested as a causativegene for autism in XLI patients with larger deletions

In our patient however the recurrent sim2Mb dele-tion (including STS PUDP MIR4767 VCX PNPLA4 andMIR651 but sparing NLGN4) was sufficient to cause bothmild autism and ADHD

Our case report highlights the importance of a neu-rological evaluation in XLI due to the association withADHDand autism especially thosewith the recurrentsim2Mbdeletions and those with larger deletions including NLGN4In addition we suggest that clinical cytogenetics laboratorieswhich report these deletions should indicate the risk forthe neurological manifestations in their interpretation inaddition to the skinmanifestations and other clinical featuresIn conclusion we hope to bring awareness of the neurologicalmanifestations of XLI among neurologists and geneticists(both laboratory and clinical)

4 Materials and Methods

Genomic DNA extraction and chromosomal microarrayanalysis were performed with the previously describedmeth-ods [14] Informed consent was obtained from themother forthe photographs

Disclosure

No statistical analysis was required

Conflicts of Interest

The authors declare that they have no conflicts of interest

References

[1] H Traupe J Fischer and V Oji ldquoNonsyndromic types ofichthyosesmdashan updaterdquo Journal of the German Society of Der-matology vol 12 no 2 pp 109ndash121 2014

[2] L Kent J Emerton V Bhadravathi et al ldquoX-linked ichthyosis(steroid sulfatase deficiency) is associated with increased riskof attention deficit hyperactivity disorder autism and socialcommunication deficitsrdquo Journal of Medical Genetics vol 45no 8 pp 519ndash524 2008

[3] K J Brookes Z Hawi A Kirley E Barry M Gill and L KentldquoAssociation of the steroid sulfatase (STS) gene with attentiondeficit hyperactivity disorderrdquo American Journal of MedicalGenetics Part B Neuropsychiatric Genetics vol 147 no 8 pp1531ndash1535 2008

[4] A Ballabio M Zollo R Carrozzo et al ldquoDeletion of the distalshort arm of the X chromosome (Xp) in a patient with shortstature chondrodysplasia punctata and X-linked ichthyosisdue to steroid sulfatase deficiencyrdquoAmerican Journal of MedicalGenetics vol 41 no 2 pp 184ndash187 1991

[5] R E Schnur B J Trask G Van den Engh et al ldquoAn Xp22microdeletion associated with ocular albinism and ichthyosisApproximation of breakpoints and estimation of deletion sizeby using cloned DNA probes and flow cytometryrdquo AmericanJournal of Human Genetics vol 45 no 5 pp 706ndash720 1989

[6] W Sedgwick ldquoOn the Influence of Sex in Hereditary DiseaserdquoTheBritish Journal of Psychiatry vol 9 no 47 pp 405ndash410 1863

[7] M Carmen Carrascosa-Romero J Suela B Alfaro-Ponce andA J Cepillo-Boluda ldquoX-chromosome-linked ichthyosis associ-ated to epilepsy hyperactivity autism and mental retardationdue to the Xp2231 microdeletionrdquo Revista de Neurologia vol54 no 4 pp 241ndash248 2012

[8] httpswwwncbinlmnihgovrefseq[9] H Ben Khelifa N Soyah I Ben-Abdallah-Bouhjar et al

ldquoXp223 interstitial deletion A recognizable chromosomalabnormality encompassing VCX3A and STS genes in a patientwith X-linked ichthyosis andmental retardationrdquoGene vol 527no 2 pp 578ndash583 2013

[10] S ACuevas-Covarrubias andLMGonzalez-Huerta ldquoAnalysisof the VCX3A VCX2 and VCX3B genes shows that VCX3Agene deletion is not sufficient to result in mental retardation inX-linked ichthyosisrdquoBritish Journal ofDermatology vol 158 no3 pp 483ndash486 2008

[11] P A Wilson S D Gardner N M Lambie S A Commansand D J Crowther ldquoCharacterization of the human patatin-like

Case Reports in Genetics 5

phospholipase familyrdquo Journal of Lipid Research vol 47 no 9pp 1940ndash1949 2006

[12] R D Strous B Spivak R Yoran-Hegesh et al ldquoAnalysis ofneurosteroid levels in attention deficit hyperactivity disorderrdquoInternational Journal of Neuropsychopharmacology vol 4 no 3pp 259ndash264 2001

[13] K J Brookes Z Hawi J Park S Scott M Gill and LKent ldquoPolymorphisms of the steroid sulfatase (STS) gene areassociated with attention deficit hyperactivity disorder andinfluence brain tissue mRNA expressionrdquo American Journal ofMedical Genetics Part B Neuropsychiatric Genetics vol 153 no8 pp 1417ndash1424 2010

[14] Y Cao and U Aypar ldquoA novel Xq221 deletion in a malewith multiple congenital abnormalities and respiratory failurerdquoEuropean Journal of Medical Genetics vol 59 no 5 pp 274ndash2772016

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom