mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review.

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

Spontaneously regressing brain lesions in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.

Prenatal presentation and diagnostic evaluation of suspected Smith-Lemli-Opitz (RSH) syndrome.

Smith-Lemli-Opitz (SLOS), or RSH syndrome, is an autosomal recessive deficiency of 7-dehydrocholesterol reductase (DHCR7) resulting in an accumulation of 7- and 8-dehydrocholesterol (7- and 8-DHC) in tissues and body fluids. At birth patients have variable malformations of CNS, heart, kidney, genitalia, and limbs, which may be life-limiting. In later course, psychomotor and mental retardation and behavior abnormalities become evident. Prenatally SLOS can be suspected on the basis of malformations and intrauterine growth retardation (IUGR) in prenatal ultrasonography and reduced maternal free estriol in serum. The diagnosis is confirmed by sterol analysis in a chorionic villus biopsy or amniotic fluid (AF). In this study, we evaluated the predictive value of the above mentioned criteria in combination with family history by quantification of sterols in AF in pregnancies with either a family history, ultrasonographical abnormalities typical for SLOS, or reduced maternal serum unconjugated estriol (MSuE3). The relative frequency of SLOS in fetuses with an affected sibling was 0.23, as to be expected for an autosomal recessive disease. The probability for SLOS was <0.6% when neither an affected sib nor more than one typical SLOS malformation was present. For safety reasons and for cost-effectiveness we recommend careful evaluation of history, MSuE3, and clinical presentation before determining sterols in AF.

Using second trimester ultrasound and maternal serum biomarker data to help detect congenital heart defects in pregnancies with positive triple-marker screening results.

Congenital heart defects (CHDs) are the most common of all birth defects. For many newborns with a CHD, prenatal versus postnatal detection is associated with substantially decreased morbidity and mortality risks. Although technological advances in fetal echocardiography have led to an increased capacity to detect CHDs prenatally, pregnancies without an identified risk factor are not routinely screened. With the aim of identifying pregnancies at increased risk for CHDs, this study examined the relationship between CHDs and typically collected second trimester biomarker data collected on a large population-based sample of singleton pregnancies with one or more second trimester screen positive result for Down syndrome, trisomy 18 (T-18), Smith-Lemli-Opitz syndrome (SLOS), or a neural tube defect (NTD). Where possible, logistic models for cases and controls were built and potential referral models were tested among study subsamples with information on the presence or absence of CHDs reported pre- and perinatally. When considered in combination, screen positive for T-18, screen positive for SLOS, nuchal fold measurement > or = 5 mm, and/or having an adjusted hCG multiple of the median > or = the 95th centile detected 42.7% of all pregnancies with a CHD in the combined subsample (where co-occurrence with chromosomal defects was not considered) and detected 29.7% of all pregnancies with a CHD in the no-chromosomal defect subsample. A nuchal fold measurement > or = 5 mm detected 18.2% of those with a CHD in the Down syndrome subsample and an adjusted hCG multiple of the median (MoM) < or = 5th centile detected 92.9% of those with a CHD in the T-18 subsample.

[Utility of fetal ultrasonography in the prenatal diagnosis of Smith-Lemli-Opitz syndrome]. / Apport de l'échographie foetale dans le diagnostic prénatal du syndrome de Smith-Lemli-Opitz.

Smith-Lemli-Opitz syndrome is a rare autosomal recessive genetic disorder which diagnosis is usually made postnatally. We describe a case of a prenatal diagnosis based only on specific ultrasound findings: intra-uterine growth retardation with facial dysmorphia, polydactyly and genital anomalies. We suggest giving more consideration to the ultrasound scanning for the diagnosis of the syndrome in the prenatal period.

Imaging findings of congenital glaucoma in Opitz syndrome.

Opitz syndrome is a rare autosomal recessive disorder of cholesterol metabolism associated with mental retardation and multiple congenital malformations. It is also uncommonly associated with congenital glaucoma. We describe the orbital findings on CT in this rare case of a patient with Opitz syndrome who presented with congenital glaucoma, with a review of the literature. The CT findings of congenital glaucoma, which have not been described before in the literature, are also discussed. It is important for the radiologist to be aware of this rare association. It is also important to be aware of the findings of congenital glaucoma on CT because patients with Opitz syndrome and other syndromes associated with learning difficulties may not present with typical clinical features of glaucoma. A high index of suspicion will lead to a correct diagnosis and earlier intervention.

Case report of unilateral clefting: is sonic hedgehog to blame?

We describe the autopsy of a chromosomally normal multiple-anomaly fetus with left side-restricted malformations, terminated after routine screening ultrasound. Autopsy findings were remarkable for severe left-sided craniofacial malformations including a cleft left frontal calavarial bone and an oblique facial cleft. Internal examination showed multiple left-sided malformations including severe left ventricular hypoplasia and interrupted aortic arch. A hypoplastic left lung, an accessory spleen, and an absent left kidney and left ureter were also discovered. Some features of the Smith-Lemli-Opitz Syndrome (SLOS) are found in this fetus, yet the occurrence of left side-restricted anomalies indicates that developmental mechanisms responsible for body laterality are involved. Potential mechanisms leading to this constellation of anomalies include a ciliary defect, side-restricted chromosomal mosaicism, or a teratogenic insult, affecting developmental morphogens, including sonic hedgehog. The sonic hedgehog pathway is important in the molecular mechanisms underlying SLOS and in laterality development in the early embryo.

Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases.

Smith-Lemli-Opitz (SLO) syndrome or RSH syndrome is an autosomal recessive multiple malformation, and mental retardation syndrome ascribed to 7-dehydrocholesterol reductase deficiency, and usually diagnosed in the early postnatal period. Reviewing a series of 30 cases of SLO, we have investigated the variable antenatal expression of the disorder. Intrauterine growth retardation (IUGR) was the most frequent detectable trait (20/30). IUGR was either isolated (9/20) or associated with at least one other anomaly (11/20), including nuchal edema, renal, cardiac, cerebral malformations, genital anomalies, or polydactyly. In this last group, 3/11 presented with multiple malformations (> or =3 anomalies). In 5/30 cases, isolated nuchal edema (3/30), and isolated cardiac (1/30) or renal malformations (1/30) were the only detectable anomalies. Ultrasound findings were considered normal in 5/30 cases and were abnormal in 25/30 cases (83%), but early detection of multiple malformations was rare (3/30, 10%). We suggest giving consideration to a more systematic sterol analysis when dealing with IUGR, especially when associated anomalies are detected.

RSH (Smith-Lemli-Opitz) syndrome: "severe" phenotype with ectrodactyly.

We describe the antenatal ultrasound findings of growth retardation, oligohydramnios, mesomelic limb shortness, and cardiac, renal, and hand defects in a fetus who was postnatally diagnosed as having RSH ("Smith-Lemli-Opitz") syndrome. An unusual finding was ectrodactyly of both hands.

Increased first trimester nuchal translucency as a prenatal manifestation of Smith-Lemli-Opitz syndrome.

Routine ultrasound examination at 11 weeks of gestation in a woman with no family history of genetic disease demonstrated increased accumulation of fluid in the fetal nuchal region. In view of the association of this defect with chromosomal abnormalities, fetal karyotyping was performed by chorion villus sampling and this demonstrated a normal 46,XY karyotype. Subsequent scans showed resolution of the nuchal fluid, and at the 20-week scan the fetal genitalia appeared to be female. Fetal blood sampling confirmed a normal male karyotype and fetoscopy confirmed the presence of female external genitalia. The parents elected to terminate the pregnancy, and postmortem findings were indicative of Smith-Lemli-Opitz syndrome. This was confirmed by the finding of increased levels of 7-dehydrocholesterol in cultured skin fibroblasts.