Impaired wound healing following cranial vault reconstruction in a patient with an atypical phenotype of Marfan syndrome: A case report.

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissues caused by mutations in the FBN1 gene which can result in widespread systemic involvement. Loeys-Dietz syndrome (LDS) is a related autosomal dominant disorder of connective tissue with widespread systemic involvement which has phenotypic overlap with MFS. LDS is caused by heterozygous pathogenic variants in six different genes, the most common of which involve transforming growth factor beta-receptor 1 or 2. While LDS is commonly associated with craniofacial manifestations, MFS is not typically characterized by craniosynostosis. Case Description: We present a 7-month-old female patient with MFS and metopic craniosynostosis with an unusual clinical presentation who underwent cranial vault reconstruction with fronto-orbital advancement and anterior cranial vault remodeling. Her course was complicated by impaired wound healing after surgery, requiring return to the operating room. Conclusion: Phenotypic overlap between genetic disorders can confound clinical diagnosis as illustrated in this case. Genetic testing can be highly valuable in the diagnosis of clinically variable disorders. Patients with MFS who undergo cranial surgery may be at increased risk for wound healing complications.

The RRAS2 pathogenic variant p.Q72L produces severe Noonan syndrome with hydrocephalus: A case report.

Noonan syndrome (NS) is the most common disease among RASopathies, characterized by short stature, distinctive facial features, congenital cardiac defects, and variable developmental delay. NS rarely presents with overt neurologic manifestations, in particular hydrocephalus. Recent evidence suggests that pathogenic variants in the gene RRAS2 are a rare cause of NS. Specifically, an RRAS2 pathogenic variant, p.Q72L, may be particularly severe, manifesting with lethal neurologic findings. Here, we report a NS patient with documented p.Q72L variant in RRAS2. The patient was identified in utero to have hydrocephalus and a Dandy Walker malformation. Postnatal examination revealed multiple dysmorphic features, some reminiscent of NS including low-set posteriorly rotated ears, redundant nuchal skin, widely spaced nipples, and cryptorchidism. Despite suspicion of NS, results of a 14-gene Noonan syndrome panel (Invitae) were negative. Follow-up rapid whole exome sequencing revealed a de novo p.Q72L variant in RRAS2, a poorly studied gene recently identified as a cause of NS. The patient herein reported brings to three the total number of cases reported with the RRAS2 p.Q72L pathogenic variant. All three documented patients presented with a particularly fulminant course of NS, which included hydrocephalus. RRAS2, specifically p.Q72L, should be considered in severe NS cases with neurologic manifestations.

Mutation update for the SATB2 gene.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

A Possible case of Facio-Auriculo-Vertebral sequence (FAVs) in an adult female from medieval Iceland (13th-16th Century).

OBJECTIVE: This paper presents a possible case of Facio-Auriculo-Vertebral sequence (FAVs) in an adult female from Haffjarðarey, Western Iceland (1200-1563 CE) and a brief review of associated terminology. MATERIALS: The skeletal remains of a single adult female (HFE-A-34, 18-24 years old), excavated in 1945 by the National Museum of Iceland. METHODS: We carried out macroscopic examination of the cranium and mandible in 2017. RESULTS: Right side unilateral asymmetric craniofacial dysplasia was identified on the cranium and mandible of HFE-A-34. CONCLUSIONS: This individual presents with anomalous craniofacial asymmetry consistent with a clinical diagnosis of FAVs. SIGNIFICANCE: This paper offers a visually distinct case of an under-represented and under-documented congenital condition for future identification within paleopathology. LIMITATIONS: Infra-cranial skeletal manifestations of FAVs would strengthen this possible diagnosis, but at this time it is not possible to definitively link the cranium and mandible of HFE-A-34 to any of the infra-cranial remains excavated from Haffjarðarey. SUGGESTIONS FOR FURTHER RESEARCH: In addition to further clarifying the variable nature of FAVs in archaeological remains, a detailed discussion of disability and the perception of disabled individuals within the medieval North Atlantic is necessary in order to understand the lived experiences of affected individuals.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia.

The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, TRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family.

Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The Action to Control Cardiovascular Disease in Diabetes (ACCORD) blood pressure trial is an unmasked, open-label, randomized trial with a sample size of 4,733 participants. This report describes the rationale, design, and methods of the blood pressure interventions in ACCORD. Participants eligible for the blood pressure trial are randomized to 1 of 2 groups with different treatment goals: systolic blood pressure <120 mm Hg for the more intensive goal and systolic blood pressure <140 mm Hg for the less intensive goal. The primary outcome measure for the trial is the first occurrence of a major cardiovascular disease (CVD) event, specifically nonfatal myocardial infarction or stroke, or cardiovascular death during a follow-up period ranging from 4-8 years. The ACCORD blood pressure trial should provide the first definitive clinical trial data on the possible benefit of treating to a more aggressive systolic blood pressure goal in reducing CVD events in patients with diabetes mellitus.

Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

BACKGROUND: Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension. The significance of this finding is uncertain. Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic, calcium-channel blocker, or angiotensin-converting enzyme inhibitor on fasting glucose (FG) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus (DM) in 3 treatment groups. METHODS: We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) among nondiabetic participants who were randomized to receive treatment with chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n = 5034) and observed for a mean of 4.9 years. RESULTS: Mean FG levels increased during follow-up in all treatment groups. At year 2, those randomized to the chlorthalidone group had the greatest increase (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing DM with lisinopril (0.55 [95% confidence interval, 0.43-0.70]) or amlodipine (0.73 [95% confidence interval, 0.58-0.91]) vs chlorthalidone at 2 years were significantly lower than 1.0 (P<.01). There was no significant association of FG level change at 2 years with subsequent coronary heart disease, stroke, cardiovascular disease, total mortality, or end-stage renal disease. There was no significant association of incident DM at 2 years with clinical outcomes, except for coronary heart disease (risk ratio, 1.64; P = .006), but the risk ratio was lower and nonsignificant in the chlorthalidone group (risk ratio, 1.46; P = .14). CONCLUSIONS: Fasting glucose levels increase in older adults with hypertension regardless of treatment type. For those taking chlorthalidone vs other medications, the risk of developing FG levels higher than 125 mg/dL (6.9 mmol/L) is modestly greater, but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events.

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Delay in diagnosis of Williams syndrome.

Williams syndrome (WS) is a well-known genetic disorder with a variable phenotype. In many cases, physical manifestations are subtle and may not be apparent at an early age, making diagnosis difficult in infants and young children who lack classic manifestations such as supravalvular aortic stenosis and hypercalcemia. Clinical suspicion is essential because the diagnostic genetic finding is not detectable on routine chromosomal analysis. Furthermore, early diagnosis allows for earlier detection and treatment of developmental, behavioral, and medical problems. In an effort to understand how and why individuals with WS are diagnosed, we conducted a survey-based study of parents of WS children. Packets containing a cover letter, consent form, parental survey and preaddressed stamped envelope were distributed to parents of children with WS. The survey included questions concerning initial diagnosis, WS findings present, medical specialists involved, and tests performed. Forty-six completed surveys were returned for analysis. The mean age at diagnosis was 3.66 years (SD 4.13). The mean age at which there were initial concerns was 0.98 year (SD 1.24) resulting in a mean delay in diagnosis of 2.77 years (SD 4.10). In addition, the involvement of a geneticists correlated with earlier diagnosis (2.26 years vs. 5.09 years without geneticist involvement, p = 0.03) and fewer tests ordered (5.2 vs. 8.2 in the nongeneticist group, p = 0.0006). We observed a significant delay in the diagnosis of WS. Of note, the involvement of a geneticist was associated with earlier diagnosis and reduced number of tests.