Smith-Lemli-Opitz Syndrome ~ Jaga Selalu Kesehatanmu

It is also known as SLO syndrome (SLOS), RSH syndrome and Rutledge lethal multiple congenital anomaly syndrome.

Description

The syndrome was first described by Smith, Lemli and Opitz in 1964.¹ The name RSH syndrome is derived from the initials of the first 3 patients to be described.

It is an inherited autosomal recessive disorder caused by mutations in the sterol delta-7-reductase gene, which maps to chromosome 11q12-q13.² It is the final enzyme in the sterol synthetic pathway that converts 7-dehydrocholesterol (7DHC) to cholesterol. Distinction was often made between a classical "type I" disorder and a more severe "type II" disorder but in reality the syndrome constitutes a clinical and biochemical continuum from mild to severe. The discovery of the deficiency of 7-dehydrocholesterol reductase as a causative factor made this the first true metabolic syndrome of multiple congenital malformations. The enzyme defect produces low plasma cholesterol and reduced myelination in the cerebral hemispheres, cranial nerves, and peripheral nerves.

Epidemiology

It occurs in relatively high frequency with approximately 1 in 20,000 to 30,000 births in populations of northern and central European background.

A study of all 86 known cases in the UK³ published in 1998 concentrated on a group of 49 with proven 7-dehydrocholesterol reductase deficiency.

In British Columbia it was found to be the second most frequent serious recessive disorder, after cystic fibrosis.

Presentation

In the UK study,³ 35 (71%) were male. At the time of study, 24 were alive, 20 had died, including 1 stillbirth, and 5 fetuses had been terminated. The minimum incidence was calculated as 1 in 60,000. The frequent occurrence of hypospadias was thought to account for the high percentage of recognised cases being male. Ambiguous external genitalia is a common feature of males and in extreme instances there is complete failure of development of male external genitalia despite normal XY karyotype.

Mental retardation was present in 23 of 25
Photosensitivity in 13 of 24
Abnormal sleep pattern in 16 of 23
Microcephaly in 32 of 40
Short or proximally placed thumbs in 24
Congenital heart disease in 18, with an atrioventricular septal defect present in 6
The typical facial appearance was found to become less obvious with age as noted elsewhere⁴
80% had 2/3 toe syndactyly

Serum 7-dehydrocholesterol levels do not correlate with clinical severity.³

There is a characteristic behaviour pattern⁵ of:

Cognitive delay
Sensory hyper-reactivity
Irritability
Language impairment
Sleep-cycle disturbance
Self-injury
Syndrome-specific motor movements
Almost universal autistic spectrum disorders⁶

Rutledge et al⁷ described what they considered to be a new lethal malformation syndrome. External features were mesomelic dwarfism (dwarfism that is characterised by shortened forearms and lower legs), micrognathia, V-shaped upper lip, microglossia, thick alveolar ridges, ambiguous genitalia, webbed neck, highly arched palate, clubfeet, fused fontanelles, inclusion cysts of the tongue, widely spaced nipples, and digital anomalies including polydactyly. Internal findings included oligopapillary renal hypoplasia, severe congenital heart defect, cerebellar hypoplasia, and pulmonary, laryngeal and gallbladder hypoplasia.

Differential diagnosis

Ambiguous Genitalia and Intersexuality
Congenital Adrenal Hyperplasia
Edwards syndrome (trisomy 18)

Investigations

Antenatal ultrasound may show intrauterine growth retardation and possibly other features too.⁸
Plasma total cholesterol and/or low-density (LDL) cholesterol levels may be low but are not always so. Measurement of plasma sterols, including at least cholesterol and 7DHC, is the diagnostic test for SLOS. The striking elevation of plasma 7DHC on sterol analysis by gas-liquid chromatography or gas chromatography/mass spectrometry is pathognomonic.
A few laboratories may be able to perform gene tests.
Electrolytes and, possibly, cortisol and ACTH may be useful in ruling out adrenal insufficiency.
Brain MRI or CT may show structural brain malformations.
Chest radiography is important in looking for congenital heart disease and/or congenital pulmonary abnormalities.
Genitourinary ultrasonography may be important in identifying genitourinary anomalies.

Management

Non-Drug

Cholesterol supplementation leads to increased plasma cholesterol levels and variable decreases in 7DHC. The Scandinavian trial of cholesterol supplementation⁹ had just 7 patients treated for between 6 months and 6 years and the results were ambivalent at best. A larger trial¹⁰ with 14 patients over 6 years did not show any benefit.

Drugs

Treatment with bile salts and even statins, despite the low cholesterol, have been tried. It is doubtful if any benefits outweigh potential toxicity.¹¹

Surgical

Congenital heart disease and polydactyly may require surgery.

Prognosis

Spontaneous abortion of affected fetuses is not unusual. Stillbirths have also been reported.
Death from multi-organ system failure during the first weeks of life is typical in the severe form.
Congenital heart disease occurs and can cause cyanosis or congestive heart failure.
Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances, and failure to thrive are common and, in some cases, related to gastrointestinal anomalies.
Visual loss may occur due to cataracts, optic nerve abnormalities, or other ophthalmic problems.
Hearing loss is fairly common.
Cause of death can include pneumonia, lethal congenital heart defect, or hepatic failure.
Survival is unlikely if the plasma cholesterol level is less than approximately 0.18 mmol/l¹² as measured by gas chromatography. This is employed because routine methods of cholesterol measurement include precursor sterols.

Prevention

Pre-natal testing with a view to termination of pregnancy is possible. Amniocentesis is performed around 15 weeks' gestation and analysis by gas chromatography-mass spectrometry demonstrates an amniotic fluid cholesterol concentration that is low and a 7-dehydrocholesterol concentration that is markedly elevated.¹³

Second trimester routine screening as an adjunct to screening for Down's syndrome does not seem very satisfactory and it would seem better to limit screening to those with a family history.¹⁴

The elevated ratio of 7-dehydrocholesterol to cholesterol in the parents suggests the possibility of identifying heterozygotes by this means.

Document references

Smith DW, Lemli L, Opitz JM:; A newly recognized syndrome of multiple congenital anomalies. J Pediatr 1964; 64: 210-21.
OMIM #270400; Smith-Lemmli-Opitz Syndrome
Ryan AK, Bartlett K, Clayton P, et al; Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. J Med Genet. 1998 Jul;35(7):558-65. [abstract]
de Die-Smulders C, Fryns JP; Smith-Lemli-Opitz syndrome: the changing phenotype with age. Genet Couns. 1992;3(2):77-82. [abstract]
Tierney E, Nwokoro NA, Porter FD, et al; Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 2001 Jan 15;98(2):191-200. [abstract]
Sikora DM, Pettit-Kekel K, Penfield J, et al; The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2006 Jul 15;140(14):1511-8. [abstract]
Rutledge JC, Friedman JM, Harrod MJ, et al; A "new" lethal multiple congenital anomaly syndrome: joint contractures, cerebellar hypoplasia, renal hypoplasia, urogenital anomalies, tongue cysts, shortness of limbs, eye abnormalities, defects of the heart, gallbladder agenesis, and ear malformations. Am J Med Genet. 1984 Oct;19(2):255-64. [abstract]
Goldenberg A, Wolf C, Chevy F, et al; Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases. Am J Med Genet A. 2004 Feb 1;124(4):423-6. [abstract]
Starck L, Lovgren-Sandblom A, Bjorkhem I; Cholesterol treatment forever? The first Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome. J Intern Med. 2002 Oct;252(4):314-21. [abstract]
Sikora DM, Ruggiero M, Petit-Kekel K, et al; Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J Pediatr. 2004 Jun;144(6):783-91. [abstract]
Starck L, Lovgren-Sandblom A, Bjorkhem I; Simvastatin treatment in the SLO syndrome: a safe approach? Am J Med Genet. 2002 Nov 22;113(2):183-9. [abstract]
Tint GS, Salen G, Batta AK, et al; Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995 Jul;127(1):82-7. [abstract]
Dallaire L, Mitchell G, Giguere R, et al; Prenatal diagnosis of Smith-Lemli-Opitz syndrome is possible by measurement of 7-dehydrocholesterol in amniotic fluid. Prenat Diagn. 1995 Sep;15(9):855-8. [abstract]
Craig WY, Haddow JE, Palomaki GE, et al; Identifying Smith-Lemli-Opitz syndrome in conjunction with prenatal screening for Down syndrome. Prenat Diagn. 2006 Sep;26(9):842-9. [abstract]