Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.
De novo variants in QRICH1 (Glutamine‐rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.
with the following addendum as a Focused Revision:We conducted a comprehensive search of the literature published between 2009, when the previous guidelines were published, and May 2020. Keywords used in PubMed included "short stature," "genetic evaluation," "short stature microarray," "short stature exome sequencing" using [All Fields] [TITLE-ABS-KEY] criteria. A total of 583 articles were found of which 539 primarily addressed the identification of genes associated with growth and gene defects associated with short stature. There were 44 articles regarding the genetic evaluation of short stature. We reviewed these articles and provide the following focused revision to the original document.
Mitochondrial diseases comprise a heterogeneous group of disorders due to dysfunction of mitochondrial respiratory chain caused by mutations in both mitochondrial and nuclear genes. EARS2 encodes mitochondrial glutamyl t-RNA synthetase responsible for attaching glutamate to its cognate mitochondrial t-RNA. Hence, EARS2 is critical for protein translation in mitochondria. Homozygous or compound heterozygous EARS2 pathogenic variants are associated with a neurological disorder characterized by leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) [1]. Patients with EARS2-related mitochondrial disease become symptomatic in infancy with characteristic MRI findings of diffuse white matter changes and symmetrical signal abnormalities in the thalamus and brain stem. Their clinical presentations fall into two groups-severe and mild. Patients in the severe group present before 6 months of age with marked neurological regression followed by clinical stagnation. Patients in the mild group present later in infancy with neurological regression, but they regain some milestones and follow a stable clinical *
Background: Graves disease (GD) is the most common cause of hyperthyroidism worldwide. The usual age of presentation is between 20-30 years, and it is more common in females. Transient hyperthyroidism does occur in infants born to mothers with GD, however, the novo GD in infants is extremely rare. We are aware of only four cases of GD in children under the age of 2 years old previously reported in the literature, with the youngest being of 18 months. Although rare, the complications can be devastating, so identifying and treating GD in infants is vital. We describe an infant who presented at 12 months of life with poor weight gain. Patient Findings: A 12-month old female patient presented with weight loss, tachycardia, diaphoresis and hypertension. She had a palpable thyroid gland without ocular changes. She was found to have an undetectable Thyroid Stimulating Hormone (TSH) with an elevated free T4 of 2.1 ng/dL (normal 0.80 - 1.50 ng/dL). She was stabilized in the intensive care unit with beta-blocker and methimazole. The diagnosis of GD was subsequently confirmed with an extremely elevated elevated Thyroid Stimulating Immunoglobulins (TSI) titer of 263 Iu/L (normal 0.00-0.55 IU/L), her TSH receptor gene was normal. At 34 months of age, her TSI titer is still elevated at 34 IU/L and she still requires methimazole to maintain a euthyroid state. She is growing and developing appropriately. Conclusion: To our knowledge, this report describes the youngest child to be diagnosed with GD in the English literature. Only four patients between the ages of 18 - 24 months have been described. Autoimmune diseases are rare in infants, the reason for which GD developed at such a young age remains unclear. Clinical signs and symptoms of hyperthyroidism in infants can be subtle and easily missed: increased growth velocity, failure to gain weight, autonomic changes, and irritability. Most patients have an enlarged thyroid gland, and some have ocular changes. The major long-term complications of undiagnosed hyperthyroidism include craniosynostosis and permanent neurocognitive damage. A high index of suspicion is needed for the recognition and prompt treatment of GD in infants, leading to better clinical outcome.
Background Autosomal dominant pseudohypoaldosteronism Type 1 (PHA-1) is a salt-wasting syndrome due to mutation in the renal mineralocorticoid receptor. Here, we report an infant with a novel mutation in NR3C2 causing PHA and associated with transient hypercalcemia. Clinical Case An ex-28 weeks (birth weight 1.35 kg) male infant admitted to the NICU had increased urine output of 6 mL/kg/hr on days of life (DOL) 9-10. Initial laboratory tests showed hyponatremia (121-127 mEq/L), hyperkalemia (5.4-8.4 mEq/L), hypochloremia (89-94 mEq/L), and hypercalcemia (11.2-11.6 mg/dL). Weight had decreased 4% from birth. On exam he was normotensive with no midline defect or hyperpigmentation; he had palpable testes bilaterally and 2 cm penile length. Sodium chloride (NaCl) supplementation 2.5 mEq/day was started on DOL 10. State newborn screen 17-OHP levels were normal. His family history was unremarkable. To further investigate the hyponatremia and hyperkalemia, serum ACTH, cortisol, aldosterone, and renin were obtained. ACTH and cortisol were 33 pg/mL and 11.4 mcg/dL, respectively. While awaiting the results of the aldosterone and renin assays, fludrocortisone was started with minimal improvement in serum sodium and hypercalcemia worsening to 12.0 mg/dL. Laboratory tests obtained to investigate the hypercalcemia included phosphorus 5.5 mg/dL, hypercalciuria (urine calcium to creatinine ratio 0.4), 25-OH vitamin D 21.0 ng/mL (normal 30-100 ng/mL), and PTH 29 pg/mL (normal 10-65 pg/mL). PTH was inappropriately normal, concerning for primary hyperparathyroidism. While awaiting the aldosterone level, it was therefore recommended to decrease fludrocortisone dose. Plasma renin activity resulted at 319 ng/mL/hr (normal 2-37 ng/mL/hr) and aldosterone at 612 ng/dL (normal 5-90 ng/dL), suggesting a diagnosis of PHA. Fludrocortisone was discontinued and NaCl supplementation was increased. A heterozygous pathogenic variant, c.2457C>A (p.Tyr819Ter), was identified in the mineralocorticoid receptor gene, NR3C2, confirming the diagnosis of autosomal dominant PHA-1. This variant has not been previously reported but meets the American College of Medical Genetics and Genomics and the Association for Molecular Pathology's criteria for pathogenicity. At his outpatient follow up at 4 months, sodium was 134 mEq/L and calcium was 10.5 mg/dL. He was continued on 1.5 grams NaCl supplementation. Conclusion We report a patient with a novel mutation in the NR3C2 gene resulting in autosomal dominant PHA-1 and associated with transient hypercalcemia. Further exacerbation of hypercalcemia was seen with addition of fludrocortisone. We suspect the etiology of the transient hypercalcemia to be secondary to excess mineralocorticoids (exogenous or endogenous) that drives PTH to increase serum calcium levels, as previously described by Vaidya et al. (1) Reference (1) Vaidya A, Brown JM, Williams JS. The renin-angiotensin-aldosterone system and calcium-regulatory hormones. J Hum Hypertens. 2015 Sep;29(9): 515-21. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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