Smith-Lemli-Opitz syndrome is a cogenital malformation syndrome. It is caused by one of a total of 70 gene mutations on chromosome 11q13.4. The disorder is autosomal recessive and is an extremely rare disease with multiple organ malformations and impaired cholesterol biosynthesis.
What is Smith-Lemli-Opitz syndrome?
Smith-Lemli-Opitz syndrome falls into the group of autosomal recessive inherited malformation syndromes. In the disease, a gene mutation causes a metabolic disorder in the biosynthesis of cholesterol. The syndrome is the most common cogenital disorder of cholesterol biosynthesis. The prevalence of the disease in Europe is between about 1:60,000 and 1:10,000, making it a rare disease, although it is one of the most common cogenital disorders of cholesterol biosynthesis. The syndrome is even rarer on the continents of Asia and Africa. The disease was first described in 1964, when the geneticists D. W. Smith, L. Lemli and J. Marius Opitz documented the symptom complex from a scientific point of view. Since then, slightly more than 300 cases have been reported. Boys are more commonly affected than girls. Presumably, the symptomatology is more mild in girls and therefore more difficult to diagnose. The disease is congenital but progressively develops from birth and is therefore characterized by different courses. The syndrome is divided into types I and II depending on the symptomatology.
Causes
The cause of Smith-Lemli-Opitz syndrome is a gene mutation that was localized in more detail in 1998. Chromosome 11q13.4 is now considered the site of the mutation, with more than 70 different mutations of this localization known to date. The type of causative mutation determines the severity and type of symptoms in individual cases. The gene in question is the 7-sterol reductase gene. S. Tint, together with his colleagues, discovered that the syndrome does not allow the body’s own production of cholesterol. This production involves the conversion of the precursor 7-dehydrocholesterol into endogenous cholesterol, which cannot function because of an enzyme defect resulting from the mutation. Therefore, there is an excess of 7-dehydrocholesterol in the organism of the affected person. At the same time, there is a general deficit of cholesterol. Because of the autosomal recessive inheritance of the syndrome, both parents must carry the defective gene and can only pass it on to a child in this way. There is a 25 percent chance that the subsequent children of parental couples with one affected child will also be affected by the malformation syndrome.
Symptoms, complaints, and signs
Children with Smith-Lemli-Opitz syndrome are born with typical craniofacial malformations, most notably microcephaly, a prominent forehead, and a small nose with a broad nasal root. In addition to an anteverted nares, microgeny is present. Cleft palate and opacities of the lens are also often seen, most notably cataract and cataract. In addition, blepharoptosis is present. Mental and cerebral maldevelopments occur during the course of the disease, resulting in mental retardation. Holoprosencephaly and irritability may also characterize the clinical picture. In addition to self-injurious behavior, the syndrome can cause autistic behavior. In addition, multiple organ malformations are present, especially those of the heart and urogenital tract. Hypospadias and cryptorchidism are the most common urogenital malformations. In addition to supernumerary fingers or toes, syndactyly of the toes may be present. Also relevant within the symptom complex are muscle hypotonia, dysphagia, and gastroesophageal reflux. Intestinal dysmotility and pyloric stenosis are also often seen. In type II of the syndrome, pseudo- hermaphroditism is present, in which the external genitalia are female, although the predominant carotype is male.
Diagnosis and course of the disease
Ultrasound examinations, as prenatal diagnostics, can record the typical physical features of Smith-Lemli-Opitz syndrome even before birth. For example, in addition to growth retardation, a heart defect or the absence of a kidney may be apparent. In the case of amniocentesis, the mutation analysis may already yield a diagnosis-confirming result.After birth, the children have a characteristic facial shape and special positions of the extremities, so that the suspected diagnosis can be made by visual diagnosis in the case of failed prenatal diagnostics. Genetic diagnosis confirms the suspicion. Differentially, fetal alcohol syndrome, Pallister-Hall syndrome, Kaufmann-McKusick syndrome, and Cornelia de Lange syndrome should be distinguished from Smith-Lemli-Opitz syndrome. Paetau syndrome, ATR-X syndrome and C syndrome, Zellweger syndrome, and hydrolethalus syndrome should also be considered for differential diagnosis. The same is true for orofacial-digital syndrome, holoprosencephaly-polydactyly syndrome, and Meckel syndrome. The life expectancy of the children depends on the cholesterol concentration and the treatability of the organ malformations. Low cholesterol levels and severe malformations make an early lethal course likely. Children with high cholesterol levels and easily treatable malformations do not have severely impaired life expectancy.
Complications
Because of Smith-Lemli-Opitz syndrome, affected individuals suffer from various malformations and deformities. These have a very negative impact on the patient’s quality of life. Especially the internal organs are affected by the malformations, so that death can often occur directly after birth. Furthermore, most patients suffer from a cleft palate and also from eye problems. Furthermore, this syndrome often leads to mental disabilities and thus to mental retardation. Most patients are thus dependent on the help of other people in their lives and can no longer cope with many things in everyday life on their own. The heart is also affected by the malformations, which can lead to sudden cardiac death. Furthermore, Smith-Lemli-Opitz syndrome also affects the genitals, so that malformations can also occur in these areas. Treatment of Smith-Lemli-Opitz syndrome can usually only be symptomatic. Complications do not occur and some of the symptoms can be limited. However, a completely positive course of the disease cannot be achieved. Whether life expectancy is limited cannot be universally predicted.
Treatment and therapy
For patients with Smith-Lemli-Opitz syndrome, lifelong social and medical care is often inevitable. Their development is usually severely delayed in the cognitive and motor domains. This results in almost all cases in a lifelong disability that does not allow independent living. Therefore, mainly a supportive treatment takes place. Parents receive psychotherapeutic support as part of these measures and ideally learn to cope with their child’s illness. Smith-Lemli-Opitz syndrome is not curable and therefore cannot be treated causally. However, since a disorder of cholesterol metabolism has been documented for the syndrome, symptomatic treatment to compensate for the cholesterol deficiency is possible. This treatment is done by cholesterol administration. The usually numerous malformations of the organs must be corrected surgically, as far as this is within the realm of possibility. An exception to this is the frequently documented multi-jointed fingers and toes, which do not necessarily require surgical intervention. Accompanying symptoms such as visual difficulties can also be treated and alleviated well today. A large proportion of those affected suffer from feeding problems such as sucking and swallowing difficulties or gastroesophageal reflux and disturbed gastrointestinal peristalsis. Therefore, a feeding tube must often be resorted to in order to ensure safe feeding. Behavioral problems may be treated with behavioral therapy.
Prevention
Parents are given the option to terminate the pregnancy after a positive prenatal diagnosis for Smith-Lemli-Opitz syndrome. Otherwise, Smith-Lemli-Opitz syndrome can only be prevented if couples have molecular genetic diagnostics performed during family planning and decide against having children of their own after evidence of the mutation is provided.
Follow-up
Follow-up in Smith-Lemli-Opitz syndrome (SLOS) is based on the severity of symptoms that occur during the course of the disease. In the majority of cases, children have feeding problems. They thrive poorly.The focus of follow-up care is therefore first of all on sufficient nutrition of the affected children by means of nasogastrically supplied high-calorie liquid feeds and the administration of sufficient cholesterol. The further course of the disease also shows underdevelopment of the brain in several affected children. This underdevelopment usually leads to a physical or mental disability of varying severity. For example, not all affected children learn to walk. To compensate for the limited mobility, aids for everyday movement (for example, wheelchairs, walking and standing aids) are provided as an aftercare measure in this case. In the case of mental symptoms such as autoaggression and hyperactivity, the therapeutically prescribed drug treatment is continued as an aftercare measure. In addition, a moderate to severe heart defect manifests itself in approximately 50 percent of all affected children in the further course of the disease. After surgery for the heart defect, electrocardiographic (ECG) and sonographic examinations are scheduled at regular intervals. For the parents of children with SLOS, medical psychological counseling and therapies are recommended. Independent living in adulthood is rather unlikely. Extensive care is expected in the follow-up of SLOS in adulthood. In addition, life expectancy may be limited due to organ malformations.
Here’s what you can do yourself
The disease is associated with numerous complaints that cause a severe reduction in quality of life. Provided that a member within the family has been diagnosed with the genetic disorder, a physician should be consulted before conceiving offspring. Possible risks should be weighed up so that prudent decisions can be made for all concerned. In addition, during pregnancy, all offered check-ups should be attended. As soon as the health impairments of the child are noticed, parents and relatives can take appropriate precautions and better prepare for the coming developments. In a large number of cases, the care and support of a Smith-Lemli-Opitz syndrome sufferer leads to an enormous challenge for the relatives. Therefore, they should know and respect their physical and emotional limits. It is advisable to consider medical care for the patient and psychotherapeutic support for the relatives. This can often lead to improvements in dealing with the disease. It must be taken into account that a stable social environment is important for the patient. In addition, the patient should always remain calm in everyday life when adversities and challenges arise. Since the affected person is incapable of independent living for the rest of his or her life, special empathy should prevail in dealing with him or her.
