Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients’ mutations suggest a genotype–phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.

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BackgroundInterest in nephrology as a career has declined dramatically over the past several years. Only 62% of nephrology fellowship positions are filled for the upcoming 2020 appointment year. The purpose of this study was to identify perceptions, attitudes, motivators, and barriers to a career in nephrology among internal medicine residents.MethodsWe recruited focus groups of internal medicine residents (N=25) from the University of Colorado, and asked questions aimed at exploring perceptions, attitudes, and barriers to a career in nephrology, and ways to increase interest in nephrology. All focus groups were conducted on the University of Colorado Denver Anschutz Medical Campus. Focus group sessions were recorded and transcribed. Thematic analysis was used to identify key concepts and themes.ResultsResidents described many barriers to a career in nephrology, including lack of exposure, lack of advances in the field, low monetary compensation, high complexity, lack of role models/mentors, and low-prestige/noncompetitive nature of the field. Most residents had no exposure to outpatient nephrology. Lack of new therapeutics was a significant deterrent to nephrology. Nephrology teaching in medical school was described as not clinically relevant and too complicated. Several residents felt they were not smart enough for nephrology. Only three residents had a role model within nephrology. Residents used the word “stigmatized” to describe nephrology, and discussed how low prestige decreased their interest in a field. Participants expressed suggestions to increase interest in nephrology through earlier and more outpatient nephrology exposure, enhanced interactions with nephrologists, and research and advancements in the field.ConclusionsResidents identified several modifiable barriers to a career in nephrology. Changing how nephrology is taught in medical school, enhancing interactions with nephrologists through increased exposure, and highlighting research and advancements in nephrology may change the perception of nephrology and increase the number of residents entering the field.

OBJECTIVERecent reports have described early endoscopic suturectomy as a treatment option for patients with syndromic craniosynostosis, but such patients often require subsequent calvarial remodeling. The authors describe their experience with this patient population and seek to identify predictors of sufficiency of endoscopic surgery alone.METHODSThe medical records of patients with syndromic craniosynostosis who underwent endoscopic repair were retrospectively reviewed. Demographic data, operative details, and follow-up data were collected.RESULTSA total of 6 patients with syndromic craniosynostosis underwent endoscopic surgery followed by helmet therapy during the study period. Of these, 3 patients were male. The involved syndromes included Crouzon, Pfeiffer, Jackson-Weiss, Muenke, Saethre-Chotzen, and craniosynostosis-3 (n = 1 each). The patients underwent endoscopic surgery at a median age of 2.1 months (range 0.9–4.1 months). The median estimated blood loss was 30 ml (range 20–100 ml), with 2 patients requiring a transfusion. The median length of stay in the hospital was 1.5 days (range 1–4 days), and the median follow-up was 29.0 months (range 16.8–81.7 months), with 1 patient (16.7%) requiring an open revision. Three patients (50%) were classified as Whitaker Category I at the last follow-up. The patients for whom additional open surgery was performed or recommended (Whitaker Category IV) were the oldest patients in the cohort, ranging from 2.6 to 4.1 months at the time of surgery.CONCLUSIONSThis series demonstrates that endoscopic surgery can be sufficient to treat syndromic craniosynostosis without subsequent open calvarial remodeling over a median follow-up period of at least 2 years. The findings suggest that younger age at the time of endoscopic surgery may be an important factor in determining the sufficiency of this procedure. Even among patients who require subsequent open calvarial remodeling, early endoscopic surgery may allow for growth and development of the brain and skull while delaying the need for open remodeling until the patient is older and can better tolerate the procedure.

We report three patients with Feingold 2 syndrome with the novel features of growth hormone deficiency associated with adenohypophyseal compression, aortic dilation, phalangeal joint contractures, memory, and sleep problems in addition to the typical features of microcephaly, brachymesophalangy, toe syndactyly, short stature, and cardiac anomalies. Microdeletions of chromosome 13q that include the MIR17HG gene were found in all three. One of the patients was treated successfully with growth hormone. In addition to expanding the phenotype of Feingold 2 syndrome, we suggest management of patients with Feingold 2 syndrome include echocardiography at the time of diagnosis in all patients and consideration of evaluation for growth hormone deficiency in patients with short stature.

Individually rare but collectively common, inborn errors of metabolism (IEMs) are genetic disorders of metabolic pathways that result in multisystem dysfunction and may reduce lifespan if untreated. The IEM patient population requires collaborative care from primary care providers such as pediatricians/general practitioners, specialists, metabolic geneticists, dietitians and genetic counselors. Ideally, a patient and his or her family would have regular access to a comprehensive care team, however, some patients may require their primary care provider to manage some aspects of their IEM-related care. There have been many advances in the diagnosis and treatment of IEMs especially since the initiation of newborn screening in the United States for phenylketonuria (PKU) in the 1960s. These advancements have resulted in individuals with IEMs living into adulthood and having children of their own, creating an aging patient population and subsequent needs across this increased lifespan. Genetic counseling is a key component in the care and education of patients with IEMs at the time of the initial diagnosis and beyond. We highlight many genetic counseling concepts and issues that need to be addressed and reassessed over the lifespan of a patient with an IEM. This review is intended to support the patient's primary care provider in recognizing these concepts and issues to reinforce for patients with IEMs in the medical home and the importance of referring for genetic counseling.

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