Smith-Lemli-Opitz syndrome (SLOS)

¿Que es Smith-Lemli-Opitz syndrome (SLOS)?

Smith-Lemli-Opitz síndrome es un trastorno genético variable que se caracteriza por un crecimiento lento tanto antes como después del nacimiento. Se cree que ocurre entre 1 en 20-60,000 nacimientos vivos.

Esta rara enfermedad también se conoce como trastorno de anomalías congénitas múltiples, que se presenta con discapacidad intelectual.

El síndrome es más común en caucásicos de ascendencia centroeuropea. Pero extremadamente raro entre las poblaciones africanas y asiáticas.

Síndrome Sinónimos:
Acrodisgenital letal Síndrome Polidactilia, reversión del sexo, hipoplasia renal y Rsh pulmonar unilobar Síndrome Anomalía congénita múltiple letal de Rutledge Síndrome Slo Síndrome

¿Qué causan los cambios genéticos Smith-Lemli-Opitz syndrome (SLOS)?

Las mutaciones en el gen DHCR7 provocan una deficiencia de la enzima 7 deshidrocolesterol reductasa. Esto conduce a niveles bajos de colesterol y al síndrome de Smith-Lemli-Opitz resultante. El síndrome se hereda con un patrón autosómico recesivo.

La herencia autosómica recesiva significa que un individuo afectado recibe una copia de un gen mutado de cada uno de sus padres, dándoles dos copias de un gen mutado. Los padres, que portan sólo una copia de la mutación genética, generalmente no mostrarán ningún síntoma, pero tienen un 25% de posibilidades de transmitir las copias de las mutaciones genéticas a cada uno de sus hijos.

¿Cuales son los principales síntomas de Smith-Lemli-Opitz syndrome (SLOS)?

Los síntomas pueden variar de leves a moderados, pero los síntomas principales del síndrome de Smith-Lemli-Opitz son problemas de comportamiento y de aprendizaje. La mayoría de las personas con el síndrome reciben un diagnóstico por separado de autismo o muestran tendencias autistas. Los comportamientos autolesivos y agresivos también suelen estar presentes en las personas con el síndrome.

Las características faciales típicas del síndrome incluyen un puente nasal ancho, mentón pequeño, orejas de implantación baja, paladar arqueado alto, labio superior largo, mandíbula pequeña, orejas grandes y párpados caídos. Algunas personas nacen con dedos de las manos o de los pies adicionales, y la fusión de los dedos 2 nd y 3 rd es una característica común del síndrome.

Otros síntomas incluyen problemas crónicos del sueño, fotosensibilidad, otros problemas sensoriales, anomalías genitales y defectos congénitos múltiples (discapacidades congénitas), incluidos los relacionados con el corazón, el tracto gastrointestinal, los pulmones y los riñones.

¿Cómo se hace la prueba a alguien? Smith-Lemli-Opitz syndrome (SLOS)?

La prueba inicial para Smith-Lemli-Opitz síndrome puede comenzar con la detección del análisis facial, a través de la FDNA Telehealth plataforma de telegenética, que puede identificar los marcadores clave de la síndrome y describa la necesidad de realizar más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista. 

Sobre la base de esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.   

Posibles rasgos / características clínicas:
Herencia autosómica recesiva, fotosensibilidad cutánea, mala succión, polidactilia postaxial de la mano, polidactilia postaxial del pie, orejas en rotación posterior, heterotopía periventricular, superposición del dedo del pie, sindactilia del dedo del pie, conducto arterioso persistente, agenesia renal, quiste renal, obstrucción de la boca ancha, hipoplasia escrotal , Otitis media recurrente, cuello corto, vagina septada, convulsiones, automutilación, pubertad precoz, esclerocórnea, nistagmo, deterioro de la audición neurosensorial, hipoplasia renal, atrofia óptica, cifosis, hipertelorismo, hipertonía, holoprosencefalia, hidrocefalia, hiperactividad, hidronefrosis cabello, útero bicorne, dedo del pie corto, hipocolesterolemia, hipoplasia de los lóbulos frontales, hipoplasia del pene, hipoplasia del cuerpo calloso, pulgar corto, hipospadias, hipotonía generalizada, glaucoma, sobrecrecimiento gingival, puente nasal deprimido, reflujo gastroesofágico, dismotilidad gastrointestinal, corta estatura, discapacidad auditiva, dedo en martillo, Microcefalia, Escoliosis

Información médica sobre Smith-Lemli-Opitz Síndrome

Smith-Lemli-Opitz syndrome is a disorder of cholesterol metabolism with a widely variable phenotype ranging from multiple congenital anomalies to normal development. The features may include microcephaly, growth retardation, cleft palate, cardiac defects, underdeveloped external genitalia in males, and 2-3 syndactyly of the toes. This autosomal-recessive disorder is caused by homozygous mutations in the DHCR7 gene on chromosome 11q13​.4. The facial features consist of microcephaly with bi-temporal narrowing, ptosis, anteverted nostrils, a broad nasal tip, prominent lateral palatine ridges, and micrognathia. Ocular abnormalities can include cataracts and optic atrophy (Atchaneeyasakul et al., 1998). In the hands, the index finger can overlap the middle finger, and the thumb can be short with a short 1st metacarpal. There is significant 2-3 syndactyly of the toes and, in males, hypospadias and a hypoplastic scrotum. Various internal malformations have been reported including pyloric stenosis, cleft palate, pancreatic anomalies, and lung segmentation defects.

The incidence of this condition has been estimated to be about 1 in 20,000 - 25,000 in a European Canadian population in Ontario (Nowaczyk et al., 2001 and Waye et al., 2002). Nowaczyk et al., (2001) found that the carrier rate for SLO in Caucasians might be as high as 1 in 30. Wright et al., (2003) reported a carrier frequency of 0.73% in African Americans.

De Die-Smulders and Fryns (1992) presented the clinical features in two adult brothers, which can be significantly different from the picture in childhood. It is instructive to look at the adult facial photographs in this paper. The diagnosis was subsequently confirmed biochemically.

There is evidence for two separate types of SLOS, one of which is lethal in the neonatal period. Cherstvoy et al., (1984) and Donnai et al., (1986) review the evidence for the severe lethal form, which is reviewed under Smith-Lemli-Opitz II.

Irons et al., (1993) and Tint et al., (1994) reported cases where plasma cholesterol concentrations were very low. 7-dehydrocholesterol was raised, however, and the authors postulated a defect in the enzyme that reduces the C-7,8 double bond of the latter intermediate.

Acosta (1994) discusses a high cholesterol diet as treatment for SLO syndrome. Jira et al., (1997) advocated a treatment regimen consisting of exchange transfusion in combination with inhibition of de novo cholesterol synthesis. Starck et al., (2002) combined a high cholesterol diet with a statin (simvastatin) in two patients. Levels of 7DHC were reduced, but one patient had a raised creatine kinase level, and the other had hepatotoxic side effects, so the drug had to be discontinued.

Tint et al., (1995) studied 24 individuals with Type I disease and found survival correlated strongly with higher plasma cholesterol levels.

Waterham et al., (1998) and Wassif et al., (1998) reported mutations in the 7-dehydrocholesterol (7-DHC) reductase gene.

Canick et al., (1997) suggest that maternal urinary estriol levels may be low, as well as maternal serum unconjugated estriol (uE3). However, they emphasize that the data on this are very sparse.

McGaughran et al., (1994, 1995), Tint et al., (1994), Abuelo et al., (1995), Mills et al., (1996), and Kratz and Kelley (1999) reported prenatal diagnosis by measuring 7-dehydrocholesterol (7-DHC) levels in amniotic fluid. Tint et al., (1998) showed that prenatal diagnosis can be carried out accurately by measuring amniotic fluid dehydrocholesterols.

It should be noted that Porter et al., (1996) report that cholesterol is covalently attached to the amino-terminal signaling domain of the hedgehog protein, which may explain some of the developmental anomalies in Smith-Lemli-Opitz syndrome.

Kolf-Clauw et al., (1996) reported a rat model by inhibiting 7-dehydrocholesterol reductase with the teratogen AY9944. The rats have features of holoprosencephaly.

Kelley et al., (1996) reported four patients with evidence of semilobar holoprosencephaly who were shown to have the biochemical features of Smith-Lemli-Opitz syndrome.

Sharp et al., (1997) carried out prenatal diagnosis by measuring 7-DHC in a chorionic villus biopsy.

Irons and Tint (1998) review the experience with prenatal diagnosis.

Anderson et al., (1998) reported a brother and sister with features of the condition but with a milder manifestation. They were found to have mildly depressed plasma cholesterol levels and increased 7-dehydrocholesterol levels, although less marked than in classical Smith-Lemli-Opitz syndrome. The parents also had significantly elevated levels of 7-dehydrocholesterol in lymphoblasts.

Nowaczyk et al., (1998) also reported three cases with milder clinical features. These were two brothers and their female first cousin. The family was not consanguineous. There appeared to be no facial features of the condition in the female cousin, and her 7-dehydrocholesterol levels were 20-25% of her affected cousins. The possibility that she might be a heterozygote was not discussed. De Die-Smulders et al., (1996) and Ryan et al., (1998) stress the variability of the condition.

Worthington and Goldblatt (1997) reported a case with oligodactyly and a cleft hand appearance. De Jong et al., (1998) reported a similar case with the severe type 2 phenotype. However, see Bodamer and Craigen (1999) for a query about the biochemical diagnosis of this case.

Charman et al., (1998) reported a 5-year-old girl with the condition who had photosensitivity.

Krajewska-Walaseek et al., (1999) also studied the phenotype at different ages. They note that an open-mouth appearance with pouting lips becomes a feature in older children.

Kelley and Hennekam (2000) provide a detailed clinical overview of the condition. Kelley and Hennekam (2000) and Nowaczyk and Waye (2001) provide good reviews of the clinical, biochemical, and genetic features.

Tierney et al., (2001) studied the behavioral phenotype in 56 cases. Eighty-nine percent had a history of repeated self-injury, 54% bit themselves, 48% had head-banging, and 54% threw themselves backwards in a characteristic upper body movement. Of the 11 subjects over 10 years of age, 27% had stereotypic stretching motions of the upper body accompanied by hand flapping. There was also hyperactivity and sleep disturbance. Fifty-three percent of the cases met the diagnostic criteria for autistic disorder.

Witsch-Baumgartner et al., (2000) reported mutations in 84 patients and provided some evidence for genotype-phenotype correlation. However, in a study of 32 patients by Yu et al., (2000) no phenotype-genotype correlation could be demonstrated.

Further cases with a mild phenotype were reported by Prasad et al., (2002); Mueller et al., (2003) (with Hirschsprung disease); and Langius et al., (2003).

It is interesting to note that the maternal apo E genotype might be a modifier of the syndrome (Witsch-Baumgartner et al., 2004).

Battaile et al., (1999) developed a PCR assay for the IVS8-1G->C mutation, which is relatively common. De Brasi et al., (1999) reported further mutations in the Italian population and evidence suggesting the T93M mutation is common in that population.

Yu et al., (2000) showed that the IVS8-1G->C splice acceptor site mutation is found in 60% of cases in the U.S. population. Waterham et al., (2000) found this mutation in 35% of affected alleles and, combining their results with the literature, suggested that 25% of affected alleles have this mutation. The IVS8-1G->C mutation was also found in individuals of Afro-Caribbean origin.

Nowaczyk et al., (2001) reported a fetus with holoprosencephaly who was shown to have the condition. There was a IVS8-1G->C homozygous mutation. Two other patients were reported where the same homozygous mutation was found. Although they had a severe phenotype, they did not have holoprosencephaly.

Nguyen et al., (2003) reported a 20-year-old male with developmental delay and physical features of Smith-Lemli-Opitz who had profound hypocholesterolemia but with normal 7DHC levels. The hypocholesterolemia was thought to be due to familial hypobetalipoproteinemia, which was present in other normal family members.

Sikora et al., (2006) also stressed the high frequency of autism or related behavioral problems in SLOS.

Note that some patients with mutations can have a very mild phenotype (Jezela-Stanek et al., 2008).

Quelin et al., (2012) identified 10 molecularly proven fetal cases and examined the pathology. Additional features found were ulnar hypoplasia, vertebral segmentation defects, gastroschisis, lung fusion, pulmonary adenomatoid malformation, and hypothalamic hamartomas. The fetal faces were typical of the syndrome.

Movassaghi et al., (2017) compared levels of 25-hydroxyvitamin D between 53 Smith-Lemli-Opitz patients and a control group. The authors found increased levels of 5-hydroxyvitamin D, as well as higher blood calcium levels, in Smith-Lemli-Opitz patients. None of the patients had vitamin D toxicity.

Prosnitz et al., (2017) described five male patients with Smith-Lemli-Opitz syndrome and pulmonary vein stenosis. Three patients died from this condition.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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