The clinical presentation of patients suffering from Smith Lemli Opitz syndrome tend to fluctuate between several phenotypes, depending on the extent of cholesterol deficiency. However, there typical findings associated with the syndrome, which include:

• Microcephaly
• Mental disability
• Hindered growth, short stature
• Polydactyly
• Conjoined toes or fingers
• Genitalia deformity or underdevelopment

Additional characteristics may also accompany SLOS. Individual often exhibit epicanthic folds, ptosis, large ears, wrinkled skin on lower and upper eyelids, vision impairment (i.e cataracts) and gum abnormalities.

Epileptic phenomena may also manifest, alongside cardiovascular problems, hypotonia in children [10] and gastroenterological issues, such as obstruction of the bowel or pyloric stenosis.

• Short Stature

  Affected individuals have dysmorphism, short stature, failure to thrive, microcephaly, multiple congenital malformations, and mental retardation. [ncbi.nlm.nih.gov]

  A syndrome with variable characteristics marked mainly by short stature, mental deficiency, microcephaly, postaxial polydactyly, cleft palate, cardiovascular defects, genital malformations, and other abnormalities associated with defective cholesterol [icd10data.com]

  stature, and intellectual disabilities) 759.89 Rud's (mental deficiency, epilepsy, and infantilism) 759.89 Russell (-Silver) (congenital hemihypertrophy and short stature) 759.89 Seckel's 759.89 sick Silver's (congenital hemihypertrophy and short stature [icd9data.com]

• Weight Gain

  In surviving infants, slow growth and poor weight gain is usual and feeding via a gastrostomy (a tube into the stomach) may be required. As the infant gets older, severe learning difficulties (see entry Learning Disability ) usually become evident. [contact.org.uk]

  SLOS is suspected because of the physical anomalies and the infant’s difficulty feeding and poor weight gain. To confirm the diagnosis, a special blood sterol test is needed. [medigoo.com]

  Consideration should be given to cholesterol supplementation to improve weight gain. [en.wikibooks.org]

  Case Report A 4-month-old African American male patient with sickle cell trait, who was being evaluated for poor weight gain and frequent regurgitation, was found to have a bifid epiglottis ( Fig 1 ) and tracheomalacia. fig 1. [ajnr.org]

  After 6 months of age, the cholesterol-supplemented mice did demonstrate increased weight gain; however, this effect was also observed in control animals that fed on the cholesterol-supplemented chow. [doi.org]

• Congestive Heart Failure

  Congenital heart disease is not uncommon in Smith-Lemli-Opitz syndrome and can cause cyanosis or congestive heart failure. [emedicine.medscape.com]

• Syndactyly of Second and Third Toes

  C. showing ambiguous genitalia and D. showing syndactyly of second and third toes. [indianpediatrics.net]

  The limbs had syndactyly of second and third toes with short and stubby fingers (Figure 4) and simian crease. Genital examination showed pen scrotal hypospadias with undescended testis (Figure 5). Systemic examination showed pan systolicmurmur. [omicsgroup.org]

• Dysmorphic Face

  We present the case of an infant born by cesarean section for fetal suffering (Apgar score 8/1′–8/5′), with multiple malformations (dysmorphic face, polydactyly, syndactyly, hypospadias, cryptorchidism) detected already at birth. [endocrine-abstracts.org]

  SLOS is characterized by growth failure, cognitive delay, behavioral disturbances, dysmorphic faces, and congenital defects. [radiologykey.com]

• Pneumonia

  Cause of death can include pneumonia, lethal congenital heart defect or hepatic failure. Prevention Measurements of amniotic fluid or chorionic villous 7DHC content can be taken. [patient.info]

  Cause of death can include pneumonia, lethal congenital heart defect, or hepatic failure. [emedicine.medscape.com]

• Failure to Thrive

  Affected individuals have dysmorphism, short stature, failure to thrive, microcephaly, multiple congenital malformations, and mental retardation. [ncbi.nlm.nih.gov]

  Feeding difficulties and failure to thrive are common. Vision loss due to cataracts and optic nerve abnormalities, and hearing loss may also occur. [secure.ssa.gov]

  Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances and failure to thrive are common. In some cases they are related to gastrointestinal anomalies. Moderate-to-severe intellectual disability is also usually seen. [patient.info]

• Constipation

  Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances and failure to thrive are common. In some cases they are related to gastrointestinal anomalies. Moderate-to-severe intellectual disability is also usually seen. [patient.info]

  Pulmonary hypertension has been noted in at least one patient. [15] Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances, and failure to thrive are common and, in some cases, related to GI anomalies. [emedicine.medscape.com]

• Heart Disease

  Chest radiography is important in looking for congenital heart disease and/or congenital pulmonary abnormalities. Genitourinary ultrasonography may be important in identifying genitourinary anomalies. [patient.info]

  The malformations present were facial dysmorphisms, cleft palate, congenital heart disease, genitourinary abnormalities, and syndactyly of the toes. [ncbi.nlm.nih.gov]

  Giuseppe Santoro, Giuseppe Pacileo, Maria Giovanna Russo Bentham Science Publishers, 11 nov. 2012 - 234 páginas Congenital heart diseases are the most common neonatal malformations, ranging from 8 to 15/1000 live births in various communities. [books.google.es]

• Hypertension

  We present a fourth patient with a severe form of SLOS and adrenal insufficiency who had unexplained persistent hypertension, a combination of signs that has not been reported previously in SLOS. [ncbi.nlm.nih.gov]

  Pulmonary hypertension has been noted in at least one patient. [15] Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances, and failure to thrive are common and, in some cases, related to GI anomalies. [emedicine.medscape.com]

• Heart Failure

  Congenital heart disease is not uncommon in Smith-Lemli-Opitz syndrome and can cause cyanosis or congestive heart failure. [emedicine.medscape.com]

• Cyanosis

  On examination, he had cyanosis, facial dysmorphism, obesity, bilateral cryptorchidism, hypospadias, inverted nipples, and systolic murmur over the left parasternal area. Investigations revealed a decreased serum cholesterol and elevated 7DHC. [ncbi.nlm.nih.gov]

  Congenital heart disease is not uncommon in Smith-Lemli-Opitz syndrome and can cause cyanosis or congestive heart failure. [emedicine.medscape.com]

• Hearing Impairment

  It is characterized by growth and developmental delay, vision and hearing impairment, and impairment of the peripheral nervous system function. [icd10data.com]

• Severe Short Stature

  Overall the best phenotypic match for Patient 3 is with the Carney Complex plus patient [43], who had few overt manifestations of Carney complex but had IUGR, feeding difficulties, global developmental delay (although not as severe), short stature ( st [journals.plos.org]

• Blepharoptosis

  Clinical Characteristics Ocular Features: A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree. No consistent pattern of ocular abnormalities has been reported. [disorders.eyes.arizona.edu]

  Blepharoptosis in children: our experience at the light of literature. Clin Ter 2010;161:241–3. [24]. Jubbal KT, Kania K, Braun TL, et al. Pediatric blepharoptosis. Semin Plast Surg 2017;31:58–64. [25]. Gutowski NJ, Chilton JK. [journals.lww.com]

  […] self-injury • central nervous system malformations • holoprosencephaly • agenesis or partial agenesis of corpus callosum • craniofacial • microcephaly • cleft palate/arched palate/bifid uvula • dysmorphic facial features (anteverted nares, micrognathia, blepharoptosis [radiologykey.com]

  Cases reported between mid 1960’s and late1970’s suggested that both male and female were affected with a autosomal recessive inheritance pattern, and additional features were blepharoptosis, genital hypoplasia, micrognathia, polydactyly, cleft palate [path.upmc.edu]

• Visual Impairment

  2 cerebral cavernous malformation 3 cerebral creatine deficiency syndrome + Cerebral Visual Impairment and Intellectual Disability cerebrocostomandibular syndrome Cerebrofaciothoracic Dysplasia Cerebrooculofacioskeletal Syndrome 2 Cerebrooculofacioskeletal [rgd.mcw.edu]

• Hypertelorism

  She had microcephaly with hypoplastic cerebral frontal lobes and cerebellum, agenesis of the splenium of corpus callosum, abnormal facies including hypertelorism with bilateral inner epicanthal folds, a broad nasal bridge with slightly anteverted nares [ncbi.nlm.nih.gov]

  It is characterized by short stature, webbed neck, hypertelorism, low-set ears, deafness, and thrombocytopenia or abnormal platelet function. [icd10data.com]

  He was noted to be slightly dysmorphic with bilateral ptosis, epicanthal folds, hypertelorism, a broad nasal bridge with anteverted nares, and posteriorly rotated ears. [bmcmedgenet.biomedcentral.com]

  microtia, facial clefting syndrome Hypertelorism, Severe, with Midface Prominence, Myopia, Mental Retardation, and Bone Fragility Hypogonadism with Low-Grade Mental Deficiency and Microcephaly hypogonadotropic hypogonadism 23 with or without anosmia [rgd.mcw.edu]

  On physical examination, C was noted to have mildly dysmorphic facial features with wide-set eyes (hypertelorism), posteriorly rotated ears, a prominent nasal bridge, a high arched palate, and upturned nares ( Figure 1 ). [doi.org]

• Narrow Forehead

  At 31 weeks of gestation, the following fetal malformations were detected on an ultrasound: atrioventricular septal defect (AVSD), aortic coarctation, shortening of the lower limbs, narrow forehead, hyperthelorism, micrognathia, anteverted nares, ambiguous [ncbi.nlm.nih.gov]

• Beaked Nose

  The craniofacial dysmorphism in patients diagnosed with this condition consists of microcephaly, a low anterior hair line, downslanting palpebral fissures, ocular signs (including ptosis, epicanthus, and strabismus), a broad nasal bridge, a beaked nose [journals.lww.com]

Smith Lemli Opitz syndrome can be diagnosed both antenatally and postnatally.

Antenatally

The first screening step is an ultrasonographic evaluation of the embryo. If features that suggest a potential SLOS are observed, 7DHC levels can be calculated through chorionic villus sampling or amniocentesis. Genetic testing can only be performed if a member of the family is affected by SLOS and, therefore, an identification of the responsible mutation is already known.

Generally, if a mother exhibits a decreased concentration of unconjugated estriol, it is considered an indication of trisomy; if, however, genetic testing reveals a normal karyotype, the finding is increasingly indicative of SLOS. Maternal urine of women pregnant with a child affected by SLOS has been found to contain equine estriols and this test is likely to render the diagnosis of the syndrome in a non-invasive way possible [11].

Postnatally

A clinical examination usually reveals findings compatible with SLOS. Further testing, including blood tests and imaging studies, is required to establish a definitive diagnosis of the condition.

An affected newborn is expected to exhibit low LDL levels and total cholesterol concentration, as well as elevated blood levels of 7DHC.

Additionally, a child has to be evaluated with a computerized tomography (CT) or magnetic resonance imaging (MRI) scan, in order to illustrate brain abnormalities, as well as a US scan for kidney deformities. The possibility of pyloric stenosis and Hirschsprung disease has to be assessed as well, with the aid of an abdominal US scan, a barium swallow and abdominal x-ray or barium enema respectively.

As of yet, there is no cure for Smith Lemli Opitz syndrome [12] and there has been no definitive suggestion either, as to the exact type of supportive treatment that will be needed.

A universally accepted fact is the necessity to treat symptoms and defects emerging from the syndrome itself. Conjoined fingers or toes and congenital cardiac defects have to be surgically treated early in the course of the disease, a pylorotomy can be performed in order to treat the stenosis and cleft palate can also be surgically corrected. Individuals may also benefit from surgical treatment if Hirschsprung disease is detected or if polydactyly is present. Hormonal supplements are administered to compensate for their low levels in the plasma and devices used to improve hearing ability will be useful to the patients suffering from hearing loss or various degrees.

With regard to the cholesterol deficiency itself, inhibitors of hydroxymethylglutaryl-coenzyme-A-reductase and cholesterol supplements have been attempted as a therapeutic procedure, but it has yet to be determined what dose should be given, which form of cholesterol supplements and whether there is a need for bile acid supplementation as well. The most important question that needs further research in order to be answered, is whether cholesterol supplement will actually benefit the patients in any way. Cholic acid supplementation has received FDA approval for the treatment of SLOS. Researchers have attempted to boost cholesterol concentration both with pharmacologically administered cholesterol compounds and cholesterol-rich food products, such as whipping cream and egg yolks.

In order to improve the chances of fetal development, IV and intraperitoneal transfusion of fresh-frozen plasma to the embryo has been attempted during pregnancy. The results were positive and it seemed that cholesterol was admitted into the red blood cells of the fetus.

Statins, which are used in healthy individuals to lower cholesterol levels in the blood, were found to not have this effect on patients with SLOS. They have been administered with the belief that they would lower 7DHC levels in the plasma, but the respective study revealed no actual benefits to the patients [13].

There is very little data on the long-term prognosis of patients suffering from SLOS. It is widely accepted that individuals who display a blood cholesterol level of <20 mg/dL have a poor prognosis and usually do not reach adulthood.

There is one well-documented case concerning one of the three patients originally described by Smith, Lemli and Opitz. The patient was monitored by another medical team in order to evaluate the progress of the disease for 30 years.

The male patient [9], who had reached adulthood, exhibited significant mental disability, epileptic phenomena and aggressive behavior; for the latter two he received drug treatment. His state of general health was very good, although typical outer appearance characteristics remained evident. He was put on an appropriate diet which increased cholesterol intake and the patient exhibited a significant improvement in terms of mood, aggressiveness and communicative skills after two months. Blood tests carried out at intervals revealed that the patient failed to maintain adequate cholesterol levels without supplementation.

SLOS is inherited with an autosomal recessive pattern [3]. Regarding the genetic mutations, 4-5 distinct mutations have been identified so far, which suggests that in cases of consanguinity, the risk of the parents carrying the same defective gene is significantly higher and therefore, careful genetic counseling must be provided before the decision to have children is made. As a general rule, carriers of the mutated genes exhibit no symptoms.

There is little consent on the matter of SLOS incidence in different parts of the world. The first calculation by Lowry and Yong showed that SLOS occurred once (1) every 40,000 births in British Columbia [4], but the rate augmented to 1 per 20,000 births when the study evaluated patients with indications towards the syndrome but no definitive diagnosis. Another research conducted in the Czech Republic calculated the incidence of SLOS as amounting to 1 per 10,000 births, a rate which is significantly higher than the two previous estimations [5].

More recent studies have shown that the SLOS incidence is considerably lower than the aforementioned numbers, namely from 1/60,000 to 1/90,000 in the USA and United kingdom respectively. It has become clear, through various studies that ethnicity plays an important role in the incidence of SLOS.

The syndrome was first described by Smith, Lemli and Opitz in 1964 [6]. Its causes where unknown at the time and it was not until 1993 [7] that it was proven that patients exhibited low levels of cholesterol in the blood and increased levels of a substance that precedes cholesterol in the maturation process, 7DHC. The gene that encodes for 7DHC (DHCR7) was found to be responsible for producing a molecular substance that cannot adequately evolve into cholesterol, rendering SLOS an inherited metabolic defect.

The functionality of cholesterol as a constructing substance was also later discovered and this discovery shed light on why the affected patients displayed the respective symptomatology. Cholesterol is now known to act as a substrate from which hormones and bile are made, as a component of cellular membranes and a myelin component. Cholesterol also acts as a trigger for the sonic hedgehog protein found in the fetus, which is involved in the construction of many fetal systems. Failure to activate the sonic hedgehog protein alongside multiple other defects in its activation and pathway are thought to be responsible for the symptoms displayed by individuals who are born with SLOS.

Patients with SLOS have also been found to have increased isoprenoids [8], whose role, however, has not yet been fully understood.

There is no way to prevent SLOS, since it is an inherited condition. Genetic counseling in families with members affected by it may lower the chances of giving birth to offspring with the syndrome.

Smith Lemli Opitz syndrome (SLOS) is an inherited condition characterized by the absence or diminished production of cholesterol, due to a lack of 7-dehydrocholesterol reductase [1]. Given that cholesterol is indispensable to the organism, as it mediates cellular structure, hormonal production and the production of digestion-related acidic compounds, its complete lack or decreased levels can affect the body's development in a variety of ways.

Children may be born with a complete inability to produce cholesterol or with very little available cholesterol; these patients exhibit a severe clinical picture. They are born with diminished muscular tone, cleft palate and a small-sized head. Dietary habits are compensated, as most display smaller-than-normal sized stomachs that lead to emesis or a defective sucking reflex. Polydactyly may be observed or fingers and toes that are conjoined. Deformities of the genitalia may also be present [2] and the individuals have varying degrees of mental retardation.

Individuals who have a moderate lack of cholesterol exhibit a milder clinical picture, characterized by hindered growth, conjoined fingers or toes and a mild mental retardation, whereas people with insignificant lack of cholesterol may also have clinically insignificant symptoms.

Smith Lemli Opitz syndrome, abbreviated as SLOS, is a congenital anomaly. Patients who have this syndrome are borne with a defective gene, which is responsible for producing a compound, 7DHC, which matures into cholesterol. The syndrome causes an abnormal type of 7DHC which cannot be transformed into cholesterol and, as a result, patients have increased 7DHC in their blood and low cholesterol.

Cholesterol is known to be a part of the cells; without it, cellular structures are incomplete and this caused innumerable problems in their function. Hormones are also produced with cholesterol and patients with this syndrome cannot produce the amount of functional hormones needed by the organism. Cholesterol also partakes in the formation of brain structures.

A person is always born with SLOS and they cannot acquire it at a later stage; however, sometimes the disease becomes evident later on in life. Symptoms depend on how much cholesterol a patient is missing and vary from insignificant to severe. Generally, typical symptomatology includes the following:

• Abnormally small head
• Mental retardation
• Fingers or toes that are joined together
• More than 5 fingers or toes
• Heart abnormalities
• Gastrointestinal defects
• Folding of the skin on the inner corner of the eye
• Wrinkled eyelids (upper or lower)
• Aggressive behavior in adults
• Vision problems (cataracts, strabismus)
• Cleft palate

SLOS can be diagnosed before a baby is born. A doctor will usually observe something abnormal on a US scan and will perform amniocentesis or other tests in order to diagnose it. Once an individual is born, the syndrome can be diagnosed by measuring cholesterol levels and the 7DHC compound in the blood.

There is no treatment for SLOS syndrome. Lots of supportive therapies have been suggested but there is no particular consent as to what should be done exactly. Further problems, like heart problems, gastrointestinal defects and finger structural abnormalities can be surgically corrected. A person may receive supplements of hormones or cholesterol or be encouraged to consume larger quantities of foods rich in cholesterol.

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