72793-160569-1-PB-Rare cause of post-squalene disorder of cholesterol biosynthesis

Nigerian Journal of Paediatrics 2012;39(1): 27 - 30

CASE REPORT

Zikavska T

Rare cause of post-squalene disorder of

Brucknerova I

Cervenova O

cholesterol biosynthesis

Bzduch V

DOI: http://dx.doi.org/10.4314/njp.v39i1.6

Received: 23rd September 2011

Abstract

Errors of cholesterol

Acetyl-CoA units are converted to

Accepted: 25th October 2011

b i o s y n t h e s i s

r e p r e s e n t

mevalonate by a series of reactions.

heterogeneous group of metabolic

Mevalonate is formed on squalene

Zikavska Tatiana ( )

disorders. The aim of the authors of

and then lanosterol. Lanosterol is

Brucknerova Ingrid

this article is to present a case of a

converted by two different

Cervenova Olga

patient with typical symptoms of a

pathways, either with the creation

Bzduch Vladimir

rare post-squalene disorder of

of 7-dehydrocholesterol, or

Department of Paediatrics, Faculty cholesterol biosynthesis, its

desmosterol with the creation of

cholesterol.

of Medicine, Comenius University, diagnostics and progress in

Limbova 1, 833 40 Bratislava,

neonatal period. The differential

Errors of cholesterol biosynthesis

Slovak Republic

diagnosis of a typical findings on

represent a heterogeneous group of

Email: zikavska@gmail.com

the skin with spontaneous

metabolic disorders that is

r e g r e s s i o n

i c h t y o s i f o r m

characterized by multiple

erythroderma, craniofacial

dysmorphic features underlining an

dysmorphic features, anomalies of

important role for cholesterol in

organs or skeletal abnormalities in

human embryogenesis and

development.

a newborn may also be the result of

a disorder of cholesterol

The differential diagnosis of

biosynthesis. The final diagnosis is

atypical findings on the skin in

definitely confirmed by

DNA

newborn may be the result of

analysis. Prognosis depends on the

d i s o r d e r

o f

c h o l e s t e r o l

different enzyme defects of

biosynthesis. It may be also

cholesterol biosynthesis pathway,

associated with various dysmorphic

but typically on the post-squalene

features or anomalies including

pathway.

multiple anomalies of congenital

Cholesterol is an important

and internal organs and skeletal

substance that plays a significant

abnormalities. Some of the post-

role in membrane structure, as well

squalene disorders may point to

as being the precursor for the

atypical findings on the skin in the

synthesis of the steroid hormones

form of psoriatic eruptions,

and bile acids. Cholesterol

psychomotoric delay or laboratory

synthesis occurs in the cytoplasm

findings as hypocholesterolemia.

and microsomes from the two-

carbon acetate group of acetyl

Key words: newborn;

coenzyme A (acetyl-CoA).

The

hypocholesterolemia; stigma;

biosynthesis of cholesterol

chondrodysplasia punctata;

consists of several reactions.

ichthyosiform erythroderma

Case report

was born by caesarean section in the 39 week of

gestation. Birth weight was 3360 grams and birth

length was 41 centimeters (corresponding to the 3

The authors present the case of a female newborn

with pathological findings. Growth retardation of

percentile).Apgar score was 10/10.

long bones and polyhydramnion in the 32 week of

Her parents were healthy. In childhood, mother was

gestation were found during pregnancy.The patient

treated with Pavlik stirrups for dysplasia

coxae congenita. Mother's height in adulthood was

cholesterol 0.66 mmol/l [Normal value < 3.4 mmol/l],

158 centimeters. Her 3-year-old elder sister was

apolipoprotein A-I 0.69 g/l [normal value 1.08 - 2.25

healthy.

g/l] and apolipoprotein B 0.47 g/l [normal value 0.50

1.30 g/l].After first week of life total cholesterol was at

At birth, short stature, asymmetrical shortening of

the level of 4.55 mmol/l. However, a mild and isolated

the femora and humeri, flat face, saddle nose, coarse

hypertriacylglycerolaemia persists in the lipid profile at

and sparse hair, wide neck with marked torticollis,

1.85 mmol/l [normal value < 1,30 mmol/l]. Complete

transversal lines on the palms with marked ulnar

blood count and CRPwere within normal levels.

deviation and right talipes equinovarus were all

noted. Large hyperkeratotic irregular linear scales on

UV spectrometry and gas chromatography/mass

erythrodermic background were found on skin (Fig

spectrometry (GC/MS) were negative. Cytogenetic

1). Cutaneous lesion reminded of a collodion baby.

examination confirmed female karyotype, 46, XX.

Molecular genetic examination detected heterozygous

Fig 1

mutation p.Trp129Term (c.386G> A) in the EBP gene

(EBP - emopamil-binding protein) encoding delta (8)-

delta(7) sterol isomerase, thereby confirming the

diagnosis of chondrodysplasia punctata type 2

(CDPX2).

Newborn with typical skin lesions of Conradi H ű nermann

Discussion

Radiography showed asymmetric shortening of the

long bones and expanded metaphyseal femur, tibia

Skeletal dysplasias form a heterogeneous group of

and epiphyseal stippling of long bones (Fig 2) and the

inherited diseases of the skeleton. They may arise from

cartilage of ribs.

disorders of metabolism of cartilage, bone or ligament.

Fig 2

According to the international classification of

osteochondrodysplasias they are divided into three

main groups, including 1. defects of long and flat bones

or axial skeleton, 2. pathological development of

cartilage and fibrous components of the skeleton, and 3.

idiopathic osteolysis.

Chondrodysplasia punctata type 2 (CDPX2) belongs to

the first group and is a clinically and genetically

heterogeneous disorder. It is characterized by

punctiform calcification of the bones. It is an X-linked

dominant genetic disorder also known as Conradi-

H ű nermann-Happle syndrome. Brachytelephalangic

Radiographic image of epiphyseal stippling of long bones

form of chondrodysplasia punctata was described by

Sheffield in 1976. It is X-linked recessive form, which

Orthopedic examination confirmed right talipes

is caused by mutation in arylsulfatase E gene (ARSE).

equinovarus with good mobility and right hip with

Zizka et al., 1998, reported two cases of rhizomelic

limited abduction, with possible dysplastic changes

chondrodysplasia punctata with distinctive phenotype

and tendency for right torticollis.

and autosomal recessive type of inheritance.

Ultrasonography detected mild dilatation of renal

pelvis of the left side. Echocardiography confirmed

Chondrodysplasia punctata type 2 is rare form of

small ventricular septal defect and foramen ovale

skeletal dysplasia. Its incidence and also prevalence is

appertum. Ophthalmologic examination excluded

unknown. In all, approximately 50 cases have been

reported in literature.

cataract and auditory emissions were without

pathological findings. Neurological examination and

ultrasonography of the brain were negative.

Molecular analysis can confirm the diagnosis. To date,

there have been descriptions in literature which

described 46 various mutations.

Laboratory tests revealed reduced total cholesterol at

In our case, the

1,87 mmol/l [normal value 2,30 4,8 mmol/l] on the

mutation of p.Trp 129Term (c.386G>A) in the EBP

second day of life.The level of HDL cholesterol was

gene encoding delta(8)-delta(7) sterol izomerase was

0,26 mmol/l [normal value < 1,68 mmol/l], LDL

detected in heterozygous state.

REVIEW

Confirmed mutation leads to a premature stop codon

Published cases in the literature have mostly been

of amino acid chain and then to a formation of

females, but X-linked dominant chondrodysplasia

truncated protein EBP with altered function

punctata may be inherited as a lethal form in

hemizygous males.

confirming the diagnosis of CDPX2. Due to the of

the gene's mutation, a defect of delta (8) - delta (7)

sterol isomerase is formed, which is an enzyme that

Other EBP mutations have been reported with no

plays an important role in the last steps of post-

evidence of correlation between phenotype of patients

with CDPX2. There are even some studies that present

squalene pathway of cholesterol biosynthesis. In this

case it was an isolated occurrence in the family.

marked variation in expressivity within the same

mutation and the same family means, which signals that

Dysmorphic features represent skin defects

the phenotypic effect of a given mutation cannot be

including linear or whorled atrophic and pigmentary

predicted, even within a family. This strong intra-

lesions, striated hyperkeratosis, coarse lusterless hair

familial variation is of paramount importance when

and alopecia, cataract and craniofacial defects.

predicting the prognosis of a particular CDPX2 patient

and providing genetic counseling to CDPX2 families.

admission of the patient in our case, large

hyperkeratotic irregular linear scales dominated on

After a complete investigation of the patient's mother, it

the skin. Skin findings improved spontaneously in

was found in our case that it was an isolated occurrence

the neonatal period. Currently, the 1-year-old girl's

of mutation.

dry skin and follicular atrophoderma especially on

the head persist.

Prenatal diagnosis is available by finding mutations on

amniocentesis or chorionic villus sampling. Kelley in

The baby in our case was born at term but Rakheja et

1999 found growth retardation, asymmetry of bone

al., 2007, reported the case of a premature female

and polyhydramnios in fetuses in the second and third

newborn with rhizomesoacromeli c limb shortening

trimesters of gestations. In our case a significant growth

of upper and lower extremities and craniofacial

retardation of long bones and polyhydramnios was

dysmorphism. Diagnosis of CDPX2 was made based

detected prenatally in our patient by ultrasonography in

the 32 week of gestation.

on elevated cholest-8(9)-en-3 β -ol in serum and

tissues. Skin changes, compared with our patient,

were not present.

Chondrodyslasia punctata type 2, known as Conradi-

H ű nermann-Happle syndrome, is an X chromosomal

Chondrodysplasia punctata type 2 is one of the six

dominant disorder of cholesterol biosynthesis. In

post-squalene disorders of cholesterol biosynthesis.

neonatal age, it is necessary to think about this post-

Herman et al., 2003 described other disorders: the

squalene disorder of cholesterol biosynthesis within the

S m i t h - L e m l i - O p i t z s y n d r o m e ( S L O S ) ,

differential diagnosis of atypical findings on the skin,

Desmosterolosis, CHILD (congenital hemidysplasia

craniofacial dysmorphic features and asymmetric

with ichthyosiform erythroderma and limb defects

shortening of extremities or skeletal abnormalities and

(syndrome) syndrome, Lathosterolosis and HEM

organ anomalies.

(hydrops-ectopic calcification-moth-eaten skeletal

dysplasia) syndrome. Among the most common

In affected patients, the analysis of sterols in plasma can

disorders of cholesterol biosynthesis in the care of

lead to the detection of accumulation of 8-

some European metabologists is SLOS.

dehydrocholesterol or cholest-8(9)-enol. Radiographic

changes show typical epiphyseal stippling of long

Gas chromatography/mass spectrometry (GC/MS)

bones, which can lead to diagnosis, but it is definitely

analysis revealed markedly elevated levels of 8-

confirmed by molecular genetic analysis.

cholest-8(9)-en- 3 β -ol and helped to identify somatic

mosaicism in a clinically unaffected men.

Clinical findings were dominated by reversible skin

lesions with spontaneous regression ichthyosiform

Sutphen et al., 1995, reported of a male patient with

Erythroderma, with the creation of systematic skin

X-linked dominant chondrodysplasia punctata and

atrophy in infancy. The prognosis of patients with

with a 47, XXY karyotype, who died at the age of 31

Conradi- H ű nermann -Happle syndrome is good.

years due to restricted pulmonary disease secondary

Psychomotor development is usually normal,

to severe kyphoscoliosis. Derry et al., 1999,

sometimes with mild retardation. Patients need

suggested that the presence of toxic sterol

dermatologic care and regular application of

intermediates may be associated with lethality in

emollients. Limb asymmetry and scoliosis can lead to

boys and assumed that some features of CDPX2

premature arthritis, which would require the

phenotype form direct defect of abnormal

cooperation with orthopedists.

cholesterol biosynthesis. The exact mechanism by

which the disrupted enzyme function leads to

Prenatal detection of significant shortening of long

impaired morphogenesis in skin, eye and bone is

bones is an indication for postnatal complete genetic

unknown.

testing.

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