Title:

Dr. William S Baek, MD

Parkside Medical Group

1310 San Bernardino Rd, Suite 102

Upland, CA 91786

Tel: 909 608 2008

Fax: 909 608 7705

E-mail: [email protected]

Abstract word count:

Manuscript word count:

This was a non-funded study.

The author has no financial relationships to disclose.

Introduction

Objective

Abstract

Keywords:

Case Presentation

A 5-year-old boy came with both parents to our clinic for a neurological evaluation. He was

enrolled in special education at a preschool level.

Pregnancy and delivery were normal. His mother remembered being told that he might have

mental retardation based on blood tests and an amniocentesis. He weighed 6 lbs 10 oz at birth,

walked at 14 months and said 'mama', 'papa' at 8-9 months. His primary language was Spanish

and speaks some English. He could count up to 100.

During early childhood he did not want to be with other children. He adhered to routines; when

dad would change his favorite Mickey Mouse TV channel he would become very angry. He

was fidgety and could not wait his turn. He could not focus in school. He was diagnosed with

attention-deficit hyperactivity disorder (ADHD) six months ago by a child psychologist.

Past medical history was significant for asthma.

He had an 11 year-old healthy sister. There was no history of consanguinity.

He was taking budesonide 0.5 mg/2 mL suspension and montelukast 4 mg daily.

He was 43.0 inches tall and weighed 42.0 lbs.

He refused to have his blood pressure checked.

Exam revealed a very bright elfin-like child (Fig. A) speaking clearly and incessantly in Spanish

in a robotic manner while wandering about in the exam room. He was able to answer questions

such as his name, age, and what he liked correctly but there was a lack of reciprocity and eye

contact. There were no tics.

He was diagnosed with ADHD and mild autism and started on amphetamine-dexoamphetamine

ER 10mg daily, which resulted in improvement in his behavior both at home and at school,

participating more in group activities. However he was still wandering around and talking

excessively in Spanish and interrupting his parents at times, hence we increased his Adderall XR

to 20mg daily, but patient became weepy and emotional hence we decreased the dose back to

10mg daily. Guanfacine 0.5mg at night was added for insomnia. His symptoms of ADHD

persisted, however, hence we increased his dose of Adderall XR to 15mg daily.

His EKG was normal. Chromosome microarray demonstrated a 1.7 MB pathogenic deletion at

Xp22.31, which included 6 genes; steroid sulfatase (STS), pseudouridine 5'-phosphatase

(PUDP), microRNA 4767 (MIR4767), variable charge, X-linked (VCX), patatin like

phospholipase domain containing 4 PNPLA4, and microRNA 651(MIR651). Hence he was

diagnosed with X linked ichthyosis (Ballabio et al, AJMG 41:184-7, 1991, Schnur et al, AJHG

45: 706-20, 1989). He tested negative for Fragile X syndrome with 29 CGG repeats.

Maternal FISH studies, test STSF (STS, Xp22.3, FISH) are suggested. Genetic consult may be of

benefit.
Discussion

This was a case of XLI with full deletion of the STS gene, which was diagnosed based on

chromosome microarray, as well as 5 other genes, presenting with autism and ADHD. Per

history his mother presumably had low or undetectable serum levels of unconjugated estriol,

which can be seen in X-linked ichthyosis, adrenal insufficiency, anencephaly, or Down

syndrome. Examining the urine for low levels of nonhydrolyzed sulfated steroids would have

been informative for diagnosing X-linked ichthyosis(Arndt ).

XLI was first described by Sedgwick in 1863. XLI occurs almost exclusively in boys; the

prevalence in Germany is approximately 1:4,000 (Traupe). XLI is due to mutation or deletion of

the steroid sulfatase(STS) gene associated with a deficiency of the enzyme STS, which is located

in the distal part of the short arm of the X chromosome (Xp22.3-pter)(Carrascosa) XLI is often

associated with ADHD(attention deficit hyperactivity syndrome)(40%) or autism (25%) or

cryptorchidism (∼20%). Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses - an

update. J Dtsch Dermatol Ges. 2014; 12(2):109-21.

The genes involved in our case of XLI

Chromosome microarray revealed a deletion of the entire STS gene, resulting in XLI. The 1.7

MB deletion in Xp22.31 also included 5 other genes; PUDP, MIR4767, VCX, PNPLA4, and

MIR651. Does not rule out balance chromosome abnormalities, or mosaicism.

1. PUDP(pseudouridine 5'-phosphatase)

Pseudouridine 5'-phosphatase encodes a member of the haloacid dehalogenase-like (HAD)

hydrolase superfamily. The encoded protein has no known biological function.

2. MIR4767(microRNA 4767)

MicroRNAs (miRNAs) are short non-coding RNAs which are involved in post-transcriptional

regulation of gene expression by affecting both the stability and translation of mRNAs. miRNAs

are transcribed by RNA polymerase II as part of capped and poly-adenylated primary transcripts

that may or may not code for proteins. The primary transcript is cleaved by the Drosophila

ribonuclease III enzyme to produce an approximately 70-nucleotide stem-loop precursor miRNA

(pre-miRNA), which is then further cleaved by the cytoplasmic Dicer ribonuclease to generate

mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is

incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs
through imperfect base pairing with the miRNA and most commonly results in translational

inhibition or destabilization of the target mRNA. [provided by RefSeq, Sep 2009]

3. VCX variable charge, X-linked

This gene belongs to the VCX/Y gene family, which has multiple members on both X and Y

chromosomes, and all are expressed exclusively in male germ cells. The X-linked members are

clustered on chromosome Xp22 and Y-linked members are two identical copies of the gene

within a palindromic region on Yq11. The family members share a high degree of sequence

identity, with the exception that a 30-bp unit is tandemly repeated in X-linked members but

occurs only once in Y-linked members. The VCX gene cluster is polymorphic in terms of copy

number; different individuals may have a different number of VCX genes. VCX/Y genes encode

small and highly charged proteins of unknown function. The presence of a putative bipartite

nuclear localization signal suggests that VCX/Y members are nuclear proteins. This gene

contains 10 repeats of the 30-bp unit. [provided by RefSeq, Jul 2008]

4. PNPLA4 (patatin like phospholipase domain containing 4)

This gene encodes a member of the patatin-like family of phospholipases. The encoded enzyme

has both triacylglycerol lipase and transacylase(N/A) activities, which may be involved in

adipocyte triglyceride homeostasis. Alternate splicing results in multiple transcript variants.

PNPLA4, which was originally described as GS2 and codes for calcium-independent

phospholipase A2 beta, has been identified as a causal gene for autism. (carrascosa)

5. MIR651 (microRNA 651)

This gene encodes microRNA 651, as previously described under MIR4767.

XLI and ADHD

XLI is often associated with ADHD(Traupe H).

Animal studies suggest that the STS gene may be involved in attentional processes.

Kent et al. reported that out of 25 boys with with either deletions and presumed point mutations

for XLI, 40% fulfilled DSM-IV criteria for ADHD, 80% of which were inattentive subtype. 5

boys fulfilled criteria for an autistic spectrum disorder or related language/communication

difficulty, and all had an unusually large deletion of the STS gene with loss of the neuroligin 4

(NLGN4) gene. None of the boys with the typical deletion or presumed point mutations of STS

demonstrated autistic difficulties.

Kent L, Emerton J, Bhadravathi V, Weisblatt E, Pasco G, Willatt LR, McMahon R, Yates JR. X-

linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention

deficit hyperactivity disorder, autism and social communication deficits. J Med

Genet. 2008;45(8):519-24.

XLI and autism

Carrascosa-Romero MC, Suela J, Alfaro-Ponce B, Cepillo-Boluda AJ. X-chromosome-linked

ichthyosis associated to epilepsy, hyperactivity, autism and mental retardation, due to the

Xp22.31 microdeletion. Rev Neurol. 2012; 54(4): 241-8.

Depending on its size, it can present as an isolated entity or combined with a syndrome caused

by neighbouring genes, thus associating itself with other monogenic diseases as well as other

mental disorders. The most relevant findings from the literature review are the importance of the

Xp22.3-pter region and the higher incidence of neurological disorders among males (attention

deficit hyperactivity disorder, autism and X-linked mental retardation). The role and implication

of these genes in the disease are discussed and the authors suggest a possible contribution of the

gene PNPLA4, which was originally described as GS2 and codes for calcium-independent

phospholipase A2 beta, involved in lipoprotein metabolism, as one of the causes of autism.

Improvements have been observed following treatment with citicoline, thanks to the role this

nootropic plays in the biosynthesis of structural phospholipids involved in the formation and

repair of the neuronal membrane.

There was no history to suggest seizures. We were unable to perform an EEG due to lack of cooperation.

Labs to check:

Lipoprotein-associated Phospholipase A2 (LabCorp Test Number: 123240 CPT: 83698)

Vitamin A levels, lipid profile, triglyceride levels, Lipoprotein Phenotyping Profile(LabCorp Test Number:
235036 CPT: 80061; 83700), ACTH, CRH, LH, FSH, GH, TSH

https://books.google.com/books?id=JpfgVgb62nsC&pg=PA64&lpg=PA64&dq=x+linked+ichthyosis,
+phosphatidylcholine&source=bl&ots=flwgrXxmvj&sig=QPcsI6aVseq13Z0K5oOiXp6QDlQ&hl=en&sa=X&
ved=0ahUKEwjfjs_Qs_bJAhURx2MKHXYmCkIQ6AEIMzAD#v=onepage&q=x%20linked%20ichthyosis%2C
%20phosphatidylcholine&f=false

Hautarzt. 2000 Jul;51(7):490-5.

[Lipoprotein and apolipoprotein electrophoresis in X-chromosome recessive ichthyosis].

[Article in German]
Arndt T1, Pelzer M, Nenoff P, Pelzer S, Lindeke A, Steinmetz A, Haustein UF.

Serum lipoprotein electrophoresis is one tool for detecting patients with recessive X-linked ichthyosis
(XRI). Compared to controls, XRI patients show elevated electrophoretic mobilities of low density (LDL)
and very low density lipoproteins (VLDL). This change in pattern is only partially explained by the
increased LDL cholesterin sulfate concentration and is the subject of this study.

The underlying cause of the increased electrophoretic mobility of VLDL and HDL in XRI patients remains
unclear.

X-linked ichthyosis can be diagnosed prenatally using fluorescence in situ hybridization.[25] Maternal
peripheral blood metaphase spreads may display 2 hybridization signals on one of the X chromosomes
(1 in the STS region [band Xp22.3] and 1 in the centromeric region), but only 1 hybridization signal (in
the X centromeric region) on the other X chromosome; therefore, one of the X chromosomes has a
deletion in the band Xp22.3 region, a result consistent with the carrier status for STS deficiency and X-
linked ichthyosis. In metaphase spreads from amniotic fluid samples, the X chromosome shows 1
hybridization signal in the control region, but no hybridization signal in the STS region. Therefore, the X
chromosome of this male fetus has a deletion in the STS region, a result consistent with X-linked
ichthyosis.

The deficit in placental STS blocks placental steroid synthesis, resulting in excretion of maternal urinary
steroids in much lower amounts than normal. Incorporating unconjugated estriol in maternal serum into
the calculation of risk increases the yield of screenings performed during pregnancy for detection of
fetal chromosomal and structural anomalies. The differential diagnosis of low and undetectable levels of
unconjugated estriol in maternal serum includes X-linked ichthyosis and serious fetal pathologies (eg,
adrenal insufficiency, anencephaly, Down syndrome). To diagnose X-linked ichthyosis, examine the urine
of these pregnant women for low levels of nonhydrolyzed sulfated steroids. X LINKED ICHTHYOSIS

http://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=8226

This is c/w a diagnosis of X linked ichthyosis(Ballabio et al, AJMG 41:184-7, 1991, Schnur et al, AJHG 45:
706-20, 1989).
Lai-Cheong JE, Elias PM, Paller AS. Pathogenesis-based therapies in ichthyoses. Dermatol Ther. 2013;
26(1):46-54.

The pathogenesis of XLI (OMIM #308100) is by far the most understood among the ichthyoses. XLI
occurs as a result of steroid sulfatase (SSase) deficiency, leading to an accumulation of cholesterol
sulfate (CSO4) in the outer epidermis (44–46), erythrocyte cell membranes (44,46), and lipoprotein
fractions of plasma (46). Whereas CSO4 levels normally comprise ~1% of lipid mass in the stratum
corneum (47,48), in XLI, CSO4 contents can reach ~10–12% (49). Although the hydrolysis of CSO4
generates some of the cholesterol required for the barrier, CSO4 is also a potent inhibitor of HMG CoA
reductase, a key enzyme involved in cholesterol synthesis, thus further reducing cholesterol levels in XLI
(49). The accumulation of CSO4 coupled with cholesterol deficiency disrupts lamellar membrane
architecture, accounting for the barrier abnormality in XLI (50,51) (Fig. 2).

Todorova A, Litvinenko I, Todorov T, Tincheva R, Avdjieva D, Tincheva S, Mitev V. A family with fragile X
syndrome, Duchenne muscular dystrophy and ichthyosis transmitted by an asymptomatic carrier. Clin
Genet. 2014 Mar; 85(3):286-9.

The human X chromosome carries regions prone to genomic instability: deletions in the Xp22.31 region,
involving the steroid sulfatase gene (STS) cause X-linked ichthyosis; rearrangements in the Xp21.2 region
are associated with Duchenne or Becker muscular dystrophies (DMD or BMD); and the Xq27.3 unstable
region, containing the (CGG)n repeat expansion in the FMR1 gene is associated with fragile X syndrome.
We report on a family with two affected boys, the elder diagnosed with fragile X syndrome, the younger
with DMD, and both suffering from severe ichthyosis. The family was analyzed by polymerase chain
reaction, multiplex ligation-dependent probe amplification and haplotype analysis. The mother proved
to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the
DMD gene and a FMR1 expansion. To the best of our knowledge, this is the first description of an
asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on
both long and short arms of the X chromosomes. The boy with fragile X syndrome has inherited a triple
recombinant maternal X chromosome, this way inheriting the FMR1 expansion and ichthyosis,
originating most probably from different maternal Xes and excluding the DMD gene deletion. The
transmission of these extremely defective maternal chromosomes to the next generation involved
several recombinations.