Download Administrative Office St. Joseph`s Hospital Site, L301

Administrative Office
St. Joseph's Hospital Site, L301-10
50 Charlton Avenue East
HAMILTON, Ontario, CANADA L8N 4A6
PHONE: (905) 521-6141
FAX: (905) 521-6142
http://www.fhs.mcmaster.ca/hrlmp/
Issue No. 44
QUARTERLY NEWSLETTER
Summer, 1998
SMITH-LEMLI-OPITZ SYNDROME:
A COMMON INHERITED DEFECT OF CHOLESTEROL
METABOLISM
Introduction
Smith-Lemli-Optiz syndrome (SLOS) is a common inherited defect of cholesterol synthesis. The birth
prevalence of SLOS in North American Caucasian population is estimated to be 1 in 10,000 to 1 in 20,000,
the third commonest recessive condition after hemochromatosis and cystic fibrosis and phenylketonuria.
Clinical Features
SLOS is characterized by microcephaly, growth retardation, dysmorphic facial features, soft tissue
syndactyly of the second and third toes, and genital abnormalities. The spectrum of severity ranges from
isolated cleft palate or minimal toe syndactyly associated with developmental delay to severely affected
newborns with multiple congenital defects incompatible with life, and sex reversal in males. Patients at either
end of the spectrum frequently escape detection either because the clinical features are so subtle or
because of demise before diagnosis is made. As the children advance in age, failure to thrive becomes
intractable, frequently necessitating tube feeding. The majority of patients do not develop speech and
require extensive care.
Genetics and Epidemiology
SLOS is inherited in a recessive fashion. The carrier frequency in the N. American Caucasian population is
estimated to be 1 in 100 to 1 in 50 (by comparison, the carrier frequency of cystic fibrosis is 1 in 22). Parents
of children with SLOS are obligate heterozygotes (carriers) and with each pregnancy have a 1 in 4 risk of
having an affected child. The gene for SLOS has been mapped to the long arm of chromosome 7
(chromosomal region 7q32.1).
Treatment
Since the biochemical defect was identified in 1994, therapy with dietary cholesterol supplementation has
shown to result in catch up growth and improvement of abnormal behaviour. Reports from multicenter trials
show that cholesterol treatment induces a marked improvement in growth and weight gain as well as
marked improvement in behaviour. There is no information available yet on the neurologic and
developmental outcomes. There are no known complications of supplementing a child’s diet with cholesterol
to treat a known cholesterol deficiency state.
The goals of therapy are to provide a suitable quantity of exogenous cholesterol in the form of dietary
cholesterol either in a natural form (eggs, cream, liver, organ meats) or as purified food grade cholesterol.
The usual starting dose is 20 to 40 mg/kg per day, which can be increased as needed. Because the diet is
unpalatable, nasogastric or gastric tubes are frequently necessary. The treatment is followed clinically by
measuring weight gain and growth rates, and biochemically by measurement of plasma cholesterol and 7dehydrocholesterol (7-DHC).
Biochemical Defect and Its Diagnosis
The underlying metabolic defect affects the final step of cholesterol synthesis. SLOS patients have a
deficiency of the enzyme 3 -hydroxysteroid- 7-reductase, which normally converts 7-dehydrocholesterol to
cholesterol. Consequently, the biochemical markers of SLOS are an abnormally low plasma cholesterol level
with a markedly elevated plasma concentration of the precursor 7-dehydrocholesterol, i.e. because of the
synthetic defect, a generalized cholesterol deficiency develops in all body tissues, and 7-DHC accumulates.
An elevated level of 7-DHC is thus diagnostic for SLOS. This test is now offered by the Biochemical
Genetics Laboratory of the HHSLP. It is performed on a fasting (overnight) serum sample. The test
requisition should read: 7-dehydrocholesterol.
Prenatal Diagnosis and Pregnancy Screening
The fetus and placenta are the source of unconjugated estradiol, a pregnancy related steroid hormone that
is derived from cholesterol and which is used as part of the routine maternal serum screen (MSS) performed
at 16 weeks of pregnancy to determine the risks of Down syndrome and open neural tube defects. In
pregnancies affected with SLOS the levels of unconjugated estradiol in maternal serum are abnormally low.
Therefore, there may be a way to screen for affected pregnancies as part of the maternal serum screen; a
multicentre NIH trial is underway to determine if this is feasible.
Prenatal diagnosis of SLOS has been successful in a number of cases using the determination of amniotic
fluid levels of 7-DHC. This analysis is also available from the Hamilton Regional Laboratory Medicine
Program - Biochemical Genetics Laboratory. Enquiries about prenatal diagnosis of SLOS, and any other
general enquiries about the diagnosis and management of this condition should be made to Dr. M.J.M.
Nowaczyk (905-521-2100, Ext. 3037).
Summary
SLOS is the second commonest recessive cause of mental retardation. It can be diagnosed rapidly and
reliably by measuring the levels of 7-DHC in the serum of affected persons. Current methods of treatment
result in improved weight gain and amelioration of behavioural problems in patients affected with SLOS.
M.J.M. Nowaczyk, MD, FRCPC, FCCMG
R.E. Hill, Ph.D.
The Hamilton Regional Laboratory Medicine Program is a collaborative program of the Hamilton Health
Sciences Corporation, St. Joseph's Hospital and McMaster University.
For further information concerning the Hamilton Regional Laboratory Medicine Program contact Mrs. Sue
Friend at (905) 521-6141.
For information on Community Laboratory Services please contact Mrs. Kathy Tiers (905) 521-6052, or the
Laboratory Reference Centre contact Mrs. Barb Baltzer at (905) 521-6065 or fax to (905) 528-1464.