Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex, also including the accessory protein, NAA15. The full spectrum of human genetic variation in this pathway is currently unknown. Here we reveal the genetic landscape of variation in NAA10 and NAA15 in humans. Through a genotype-first approach, one clinician interviewed the parents of 56 individuals with NAA10 variants and 19 individuals with NAA15 variants, which were added to all known cases (N = 106 for NAA10 and N = 66 for NAA15). Although there is clinical overlap between the two syndromes, functional assessment demonstrates that the overall level of functioning for the probands with NAA10 variants is significantly lower than the probands with NAA15 variants. The phenotypic spectrum includes variable levels of intellectual disability, delayed milestones, autism spectrum disorder, craniofacial dysmorphology, cardiac anomalies, seizures, and visual abnormalities (including cortical visual impairment and microphthalmia). One female with the p.Arg83Cys variant and one female with an NAA15 frameshift variant both have microphthalmia. The frameshift variants located toward the C-terminal end of NAA10 have much less impact on overall functioning, whereas the females with the p.Arg83Cys missense in NAA10 have substantial impairment. The overall data are consistent with a phenotypic spectrum for these alleles, involving multiple organ systems, thus revealing the widespread effect of alterations of the NTA pathway in humans.

Siblings with profound connective tissue disease: First report of biallelic TGFBR1-related Loeys-Dietz syndrome.

Heterozygous missense variants in TGFBR1, encoding one subunit of the transforming growth factor-beta receptor, are a well-established cause of Loeys-Dietz syndrome (LDS)-an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life-threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of TGFBR1-related disease. Each born at 38 weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66 days of age and Patient 2 is alive at 4 years and 4 months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF-ß responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of TGFBR1 (c.239G>A; p.Arg80Gln paternal and c.313C>G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS-an established autosomal dominant disease. These siblings represent the first reports of biallelic TGFBR1-related LDS and expand the differential diagnosis of CDH.

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome.

GTF2IRD1, a gene on chromosome 7 which encodes a transcription factor, is of significant clinical interest due to its heterozygous loss as part of the classical deletion associated with Williams-Beuren syndrome (WBS). However, biallelic variants in GTF2IRD1 alone as part of an autosomal recessive disease have not been previously reported. Here, we present two full brothers with variants in trans of GTF2IRD1 at c.1231C > T (p.Arg411Trp) and c.2632C > G (p.Leu878Val). A detailed clinical phenotype is described, which includes severe neurodevelopmental disability, facial dysmorphology, and pectus excavatum. Importantly, out of eight full siblings, only these two brothers harboring both variants in trans present with the profound described phenotype. We present the possibility that these brothers represent the identification of a new syndrome characterized by biallelic variants in GTF2IRD1, which may also have important implications for the molecular etiology of WBS.

Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 cause a Multisystem Fibroproliferative Response.

Background: Myhre syndrome, caused by pathogenic variants in SMAD4, is characterized by compact body habitus with short stature, distinctive craniofacial appearance, stiff skin, cardiovascular abnormalities (valve stenosis, coarctation, hypoplasia, or stenosis of aorta), effusions of potential spaces (pericardium, pleura, peritoneum), restricted movement of the joints (including thorax), and hearing loss. Lung and airway disease has been reported, but not always well-defined, to include interstitial lung disease, large airway obstruction, and pulmonary arterial hypertension. Excessive fibroproliferation of tissues especially following trauma or surgical instrumentation has been recognized, although these may also present spontaneously. Method: We report the pathologic features of 1 new patient with progressive choanal stenosis, and 22 literature cases, including the expanded history of 5 patients (3 who died). Results: Examination of patient tissues documents cellular fibroproliferation and deposition of excessive extracellular matrix explaining some of the observed clinical features of Myhre syndrome. Conclusion: Excessive fibrosis is noted in multiple tissues, especially heart, lung, and upper and lower airways. Our research provides the first systematic review to provide a knowledge base of gross and pathologic findings in Myhre syndrome.

CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum.

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.

Vascular dissection in women with Turner syndrome.

BACKGROUND: The frequency of ascending aortic dissection in patients with Turner syndrome in the United States remains largely unknown with data surmised from published case reports or case series. Dissection of other vascular structures has only rarely been reported in this patient cohort. Recent European data identified aortic dissection to be a relatively rare event in a group of adult women with Turner syndrome. We sought to evaluate the prevalence of, and risk factors for, vascular dissection in women with Turner syndrome followed in the United States. METHOD: Retrospective review of all adult patients (age > 18 years) with Turner syndrome seen by any medical care provider within 2 medical systems covering a 5 state referral base was performed. Demographic, clinical, surgical and imaging variables of interest were recorded. RESULTS: Vascular dissection occurred in 16 (4.1%) of the 393 adult women and prophylactic aortic replacement occurred in 14 (3.5%). Only 35% of patients were under the care of a cardiologist with the remainder followed exclusively by other care providers. Vascular dissections occurred in the ascending & descending aorta as well as pulmonary artery and cerebral vessels. In addition to bicuspid aortic valve, and prior cardiac surgery, risk factors for vascular dissection included rural residence and lack of ongoing care by a cardiologist. CONCLUSION: Transition to adult cardiology subspecialty care is lacking in patients with Turner syndrome. Aortic dissection is not uncommon. Ongoing interaction with a cardiologist is essential to optimize cardiac outcomes in those with cardiac risk factors and may best be accomplished with centralized multidisciplinary clinics.

Interdisciplinary care of children with trisomy 13 and 18.

Children with trisomy 13 and 18 (previously deemed "incompatible with life") are living longer, warranting a comprehensive overview of their unique comorbidities and complex care needs. This Review Article provides a summation of the recent literature, informed by the study team's Interdisciplinary Trisomy Translational Program consisting of representatives from: cardiology, cardiothoracic surgery, neonatology, otolaryngology, intensive care, neurology, social work, chaplaincy, nursing, and palliative care. Medical interventions are discussed in the context of decisional-paradigms and whole-family considerations. The communication format, educational endeavors, and lessons learned from the study team's interdisciplinary care processes are shared with recognition of the potential for replication and implementation in other care settings.

The QT Interval in Patients With the Turner Syndrome.

Patients with the Turner syndrome (TS) often have longer QT intervals compared with age-matched peers although the significance of this remains unknown. We sought to determine the degree, frequency and impact of QTc prolongation in patients with TS. A chart review of all patients with an electrocardiogram (ECG) and genetically proven TS was performed. Medications at the time of the ECG were reviewed and QTc calculated. Medications were classified according to QTc risk using www.crediblemeds.com. ECG parameters were compared with an age, gender, and cardiac lesion-matched control group. Over the 10-year period of review, 112 TS patients with a mean age of 34 ± 25 years underwent 226 ECGs. At least 1 QTc prolonging medication was prescribed in 81 (74%) patients. Longer QTc interval correlated with absence of y chromosomal material (p = 0.01), older age (p <0.0001), increased number of QTc prolonging and nonprolonging medications (p <0.0001 each). During the 7.0 ± 5.1 years of follow-up, no patient had ventricular arrhythmia or unexplained sudden death. QTc was significantly shorter in matched controls using either Bazett or Hodges formula (424 ± 16 ms vs 448 ± 28 ms, p <0.0001; and 414.8 ± 16 ms vs 424.2 ± 20 ms; p = 0.0002, respectively). However, there was no difference in the frequency of QTc prolongation >460 msec (2.8% vs 2.6%, p = 0.9). In conclusion, despite frequent use of QT-prolonging medications, ventricular arrhythmias are rare in TS.

Kawasaki Disease in a Patient With Williams Syndrome.

Kawasaki disease can be difficult to diagnose in infants, putting them at higher risk for developing coronary artery dilatation. It can be even more difficult to diagnose in the setting of preexisting cardiac anomalies such as those found in Williams syndrome. We present a case of a three-month-old male with Williams syndrome with rapidly developing giant coronary aneurysms due to Kawasaki disease. This case demonstrates the importance of repeat echocardiography in diagnosing incomplete Kawasaki disease in infants. We speculate that elastin changes, as present in Williams syndrome, may put affected children at higher risk for development of giant coronary arteries should they acquire Kawasaki disease.

Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome.

Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.

Hb Gibbon [ß124(H2)Pro→Thr (HBB: c.373C>A, p.P125T)], an Asymptomatic Novel Hemoglobin Variant Detected by Newborn Screening.

We describe here a previously unreported hemoglobin (Hb) variant, Hb Gibbon [ß124(H2)Pro→Thr (HBB: c.373C>A, p.P125T)] detected by newborn Hb screening in a term male with no family history for hemoglobinopathy or other screening abnormalities. This missense mutation produces a ß-globin chain variant that was detected by high performance liquid chromatography (HPLC) methods, but is silent by capillary electrophoresis (CE). DNA sequencing studies revealed that his father was also a heterozygote for this mutation. Neither has abnormalities on complete blood count (CBC) or any symptomatology.

Utilization of echocardiography in Ehlers-Danlos syndrome.

OBJECTIVES: This study assessed the frequency and utility of echocardiographic examination in patients with all forms of Ehlers-Danlos syndrome and sought to identify clinical variables associated with an abnormal echocardiogram. DESIGN/SETTING: This was a retrospective study of all patients carrying a diagnosis of Ehlers-Danlos syndrome of any type who were evaluated by a pediatrician or pediatric subspecialist at a single tertiary medical center with an affiliated children's hospital during the period January 2013 to December 2018. PATIENTS: Chart review was performed on all patients carrying a diagnosis of Ehlers-Danlos syndrome in the electronic medical record. OUTCOME MEASURES: Data from genetics examination, cardiovascular examination where applicable, genetic test results when available, and echocardiography were recorded. RESULTS: Of 262 patients identified, echocardiography and cardiac evaluation were common occurring in 90% and 50% of patients with any form of Ehlers-Danlos syndrome. Cardiovascular complications occurred in 50% of patients with vascular Ehlers-Danlos syndrome but echocardiography was normal in all. Aortic dilation was common in classic Ehlers-Danlos syndrome but absent in hypermobile Ehlers-Danlos syndrome. Mitral valve prolapse and bicuspid aortic valve occurred at the same incidence as the general population. Cardiac symptoms were present in 12% but did not correlate with abnormal cardiac structure. Presentation with symptoms of musculoskeletal pain was inversely related to the presence of cardiac pathology. CONCLUSIONS: In light of the absence of cardiac pathology in patients with hypermobile Ehlers-Danlos syndrome, routine cardiac evaluation and echocardiography are not required for patients with hypermobile Ehlers-Danlos syndrome.

PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype.

PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH. There are two previous patients reported with homozygous and apparently deleterious PIGQ mutations. Here, we provide the first detailed clinical report of a patient with heterozygous deleterious mutations associated with glycosylphosphatidylinositol-anchored protein (GPI-AP) biosynthesis deficiency. Our patient died at 10 months of age. The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia. This clinical report describes a new and rare disorder-PIGQ GPI-AP biosynthesis deficiency syndrome.

Patient with anomalous skin pigmentation expands the phenotype of ARID2 loss-of-function disorder, a SWI/SNF-related intellectual disability.

ARID2 loss-of-function is associated with a rare genetic disorder characterized in 14 reported patients to date. ARID2 encodes a member of the SWItch/sucrose non-fermentable chromatin remodeling complex. Other genes encoding subunits of this complex, such as ARID1A, ARID1B, and SMARCA2, are mutated in association with Coffin-Siris syndrome (CSS) and Nicolaides Baraitser syndrome (NCBRS) phenotypes. Previously reported ARID2 mutations manifested clinically with a CSS-like phenotype including intellectual disability, coarsened facial features, fifth toenail hypoplasia, and other recognizable dysmorphisms. However, heterogeneity exists between previously reported patients with some patients showing more overlapping features with NCBRS. Herein, we present a patient with a novel disease-causing ARID2 loss-of-function mutation. His clinical features included intellectual disability, coarse and dysmorphic facial features, toenail hypoplasia, ADHD, short stature, and delayed development consistent with prior reports. Our patient also presented with previously unreported clinical findings including ophthalmologic involvement, persistent fetal fingertip and toetip pads, and diffuse hyperpigmentary and hypopigmentary changes sparing his face, palms, and soles. The anomalous skin findings are particularly of interest given prior literature outlining the role of ARID2 in melanocyte homeostasis and melanoma. This clinical report and review of the literature is further affirming of the characteristic symptoms and expands the phenotype of this newly described and rare syndrome.

Valve-Sparing Root and Total Arch Replacement for Cutis Laxa Aortopathy.

Aortic aneurysms requiring surgery in early childhood are rare. Herein we describe the case of a three-year-old with massive aneurysmal aortic dilation secondary to the rare and often lethal genetic disorder, cutis laxa. Initial thoracic aortic aneurysm gene panel was negative. Parents of the child were not known to be consanguineous, but high-density SNP array revealed several regions of homozygosity. This prompted targeted sequence analysis that identified a novel homozygous missense mutation in the gene for cutis laxa, EFEMP2. The patient underwent aortic valve-sparing aortic root and ascending aorta replacement and total aortic arch replacement, with continuous, moderately hypothermic cardiopulmonary bypass, using a dual cannulation technique. He was discharged well on the third postoperative day and remains free of aneurysmal disease at two-year follow-up.

Eliciting Narratives to Inform Care for Infants With Trisomy 18.

: media-1vid110.1542/5804913218001PEDS-VA_2018-0321Video Abstract.

Clinical and Echocardiographic Prevalence and Detection of Congenital and Acquired Cardiac Abnormalities in Girls and Women with the Turner Syndrome.

The prevalence of congenital and acquired heart disease in patients with the Turner syndrome (TS) is based on historic cohorts who underwent imaging before the advent of modern day echocardiography. Recent small studies suggest a higher prevalence of cardiac defects. We reviewed clinical and echocardiographic data on 564 girls and women with TS to assess the prevalence of cardiac defects. Echocardiographic review on a subset of this population was performed to assess for diagnostic limitations of echocardiography in assessing for congenital and acquired defects in this patient cohort. Bicuspid aortic valve was present in 39%, aortic coarctation in 21%, and some forms of structural cardiac anomaly in 56%. Failure to perform a complete congenital echocardiogram with suprasternal and high right or left parasternal windows was associated with failure to identify congenital and acquired cardiac defects. In conclusion, major cardiac defects are present in the majority of patients with TS. Echocardiographic technique can be optimized to avoid missing cardiac lesions of potential hemodynamic significance.