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Objective: To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith–Lemli–Opitz syndrome (SLOS), after exclusion of chromosomal anomalies.
Case report: A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for f...
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Context 1
... counseling about prognosis and recurrence risks for holoprosencephaly in the prenatal period is difficult due to extreme phenotypic variability and etiological heterogeneity [2]. In fact, although it is clear that neurodevelopmental outcome and mor- tality risk depend largely on the severity of holoprosencephaly, the prognosis also hinges on the etiology, which includes environ- mental factors and teratogens, chromosomal anomalies and monogenic syndromes (Table 1), and their associated features [1,3,4]. Furthermore, an etiological diagnosis is centermost to establishing the mode of inheritance and clarifying recurrence risks. ...
Citations
... A classic example of a monogenic disorder related to syndromic HPE is Smith-Lemli-Opitz syndrome (SLOS), associated with biallelic pathogenic variants DHCR7 [67][68][69][70][71]. SLOS is caused by a deficiency of the enzyme 7-dehyrocholestol (DHC) reductase, resulting in a block in the last step of cholesterol synthesis [55]. ...
... Cholesterol modification of the SHH ligand is required for its full signal transduction activity [72]; therefore, low cholesterol has been proposed to affect the SHH signaling pathway. Clinically, patients with SLOS typically present characteristic facial features, growth delay, microcephaly, polydactyly, syndactyly of the second and third toes, cleft palate, underdeveloped external male genitalia and intellectual disability [71]. ...
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.
... No specific DHCR7 genotypephenotype correlation has been identified but most reported cases carry two null variants. [11][12][13][14] However, there have been other reported cases of homozygous null variants in DHCR7 with no reported holoprosencephaly. 14 Weaver et al 14 speculated that concomitant variants in DHCR7 and one of the genes causing nonsyndromic holoprosencephaly, including SHH (sonic hedgehog gene) may be the underlying mechanism resulting in holoprosencephaly. ...
Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder caused by variants in the DHCR7 gene. In cholesterol biosynthesis, 7‐dehydrocholesterol (7‐DHC) is converted to cholesterol by the enzyme 7‐DHC reductase, which is encoded by the gene DHCR7. Thus, an elevated 7‐DHC is indicative of SLOS. Characteristically SLOS is usually associated with congenital anomalies, dysmorphisms, and moderate to severe neurodevelopmental delay. However, there are rare descriptions of individuals with milder phenotypes. We report a mild case of SLOS presenting with short stature, cleft palate, imperforate anus, and mild language delay with subtle dysmorphic features. 7‐DHC was not elevated at 1 year of age and SLOS considered excluded at this time. The parents had two pregnancies with holoprosencephaly. Whole exome sequencing of one of the fetuses identified compound heterozygous pathogenic variants in the DHCR7 gene (c.964‐1G>C (p.?) and c.1039G>A (p.Gly347Ser) causative of SLOS. The proband with a mild form of SLOS was also found to have the same DHCR7 variants as the fetus and repeat testing of 7‐DHC at 4 years of age was elevated, in keeping with SLOS. This case is the first to describe a wide intrafamilial phenotypic spectrum of SLOS as a result of the same DHCR7 genotype. This case also supports the findings of others that a normal or near normal development should not exclude SLOS. As demonstrated in this case exclusion of a metabolic diagnosis because of a negative biochemical marker such as 7‐DHC is not absolute and if clinical suspicion remains genomic sequencing is warranted.
... Three fetuses had a severe phenotype without specific details [4]. The other eight fetuses are described in details with severe multiple various malformations [4,[9][10][11][12][13]. Three had thickened nuchal translucency (3, 3.2, and 4.2 mm), while in the other five fetuses it was not reported (Supplementary Table 2). ...
The founder variant DHCR7:c.964-1G>C causing autosomal recessive Smith–Lemli–Opitz (SLOS) was introduced into the Israeli preconception carrier program for Ashkenazi Jews in 2017 because of the high carrier frequency in this population (2.3%). Other disease-causing variants in DHCR7 are relatively rare in Israeli population. Discrepancy between the carrier frequency and disease prevalence raises the question of the actual risks for affected offspring for couples detected by the screening program. We performed a literature review of all relevant publications regarding homozygous DHCR7:c.964-1G>C fetuses/patients. We also collected clinical data about couples identified in the national screening program, including reproductive history. Out of 32 homozygous fetuses, six died in utero, 11 pregnancies were terminated during second trimester, and 15 children were born. All died between first days of life till 3 months of age. Reproductive history of SLOS-at-risk couples showed that after correction for ascertainment bias, out of 61 pregnancies, there was an absence of affected fetuses/children and an excess of miscarriages even if assumed that all the homozygous fetuses were miscarried. Out of these, eight families were Israelis, they had a total of one sick child, 21 healthy children, and 21 miscarriages. Our observations support the previous knowledge that homozygosity for c.964-1G>C in DHCR7 leads to a severe phenotype or early miscarriage. An unexpected observation was the excess of early miscarriages. This phenomenon is unclear and awaits further studies.
... Weaver et al., observed a first case of SLOS with cyclopia. 7DHCR gene analysis was performed in five of the 11 biochemically proven HPE cases, showing null alleles, deletions and nonsense mutations (Nowaczyk, McCaughey, Whelan, & Porter, 2001;Petracchi, Crespo, Michia, Igarzabal, & Gadow, 2011;Travessa, Dias, Rocha, & Sousa, 2017;Weaver, Solomon, Akin-Samson, Kelley, & Muenke, 2010). In one SLOS case HPE had developed in the presence of a nonsense and two missense mutations (Quélin et al., 2012). ...
Background:
Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.
... SLOS is a multiple congenital anomaly syndrome that presents with intellectual disability, facial dysmorphisms, congenital heart anomalies, and external genitalia defects in males. Multiple case reports have associated SLOS with HPE(Caruso et al., 2004; Kelley et al., 1996;Nowaczyk et al., 2001;Travessa, Dias, Rocha, & Sousa, 2017;Weaver, Solomon, Akin-Samson, Kelley, & Muenke, 2010). Even though only 5% of individuals with SLOS present with HPE(Caruso et al., 2004), it remains the classic example of a single gene variant associated with syndromic HPE, and its cholesterol metabolism perturbation makes this syndrome more interesting. ...
Holoprosencephaly (HPE) is partial or complete failure of the forebrain to divide into hemispheres and can be an isolated finding or associated with a syndrome. Most cases of HPE are associated with a syndrome and roughly 40%–60% of fetuses with HPE have trisomy 13 which is the most common etiology of HPE. Other syndromes associated with HPE include additional aneuploidies like trisomy 18 and single gene disorders such as Smith–Lemli–Opitz syndrome. There are a number of syndromes such as pseudotrisomy 13 which do not have a known molecular etiology; therefore, this review has two parts: syndromes with a molecular diagnosis and syndromes where the etiology is yet to be found. As most HPE is syndromic, this review provides a comprehensive list and description of syndromes associated with HPE that may be used as a differential diagnosis and starting point for evaluating individuals with HPE.
