RESUMEN
Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome.
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Algoritmos , Registros Electrónicos de Salud , Síndrome de Turner/diagnóstico , Adolescente , Niño , Preescolar , Diagnóstico Precoz , Femenino , HumanosRESUMEN
CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.
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Insuficiencia Suprarrenal/genética , Insuficiencia Suprarrenal/patología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/patología , Trastornos del Crecimiento/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Anomalías Urogenitales/genética , Anomalías Urogenitales/patología , Insuficiencia Suprarrenal/clasificación , Retardo del Crecimiento Fetal/clasificación , Humanos , Masculino , Mutación , Osteocondrodisplasias/clasificación , Fenotipo , Síndrome , Anomalías Urogenitales/clasificaciónRESUMEN
INTRODUCTION: Short stature is one of the most common reasons for referral to a pediatric endocrinologist and can result from many etiologies. However, many patients with short stature do not receive a definitive diagnosis. OBJECTIVE: To ascertain whether integrating targeted bioinformatics searches of electronic health records (EHRs) combined with genomic studies could identify patients with previously undiagnosed rare genetic etiologies of short stature. We focused on a specific rare phenotypic subgroup: patients with short stature and elevated IGF-I levels. METHODS: We performed a cross-sectional cohort study at three large academic pediatric healthcare networks. Eligible subjects included children with heights below -2 SD, IGF-I levels >90th percentile, and no known etiology for short stature. We performed a search of the EHRs to identify eligible patients. Patients were then recruited for phenotyping followed by exome sequencing and in vitro assays of IGF1R function. RESULTS: A total of 234 patients were identified by the bioinformatics algorithm with 39 deemed eligible after manual review (17%). Of those, 9 were successfully recruited. A genetic etiology was identified in 3 of the 9 patients including 2 novel variants in IGF1R and a de novo variant in CHD2. In vitro studies supported the pathogenicity of the IGF1R variants. CONCLUSIONS: This study provides proof of principle that patients with rare phenotypic subgroups can be identified based on discrete data elements in the EHRs. Although limitations exist to fully automating this approach, these searches may help find patients with previously unidentified rare genetic disorders.
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Estatura/genética , Trastornos del Crecimiento/genética , Factor I del Crecimiento Similar a la Insulina/análisis , Fenotipo , Adolescente , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Proteínas de Unión al ADN/genética , Registros Electrónicos de Salud , Femenino , Células HEK293 , Humanos , Masculino , Mutación Missense , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/fisiología , Secuenciación del ExomaRESUMEN
Context: The pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulinlike growth factor binding proteins 3 and 5, releasing free insulinlike growth factor 1 (IGF-1). Homozygous mutations in PAPP-A2 result in growth failure with elevated total but low free IGF-1. Objective: To determine the 24-hour pharmacokinetic (PK) profile of free and total IGF-1 after a dose of recombinant human insulinlike growth factor 1 (rhIGF-1). We describe the growth response and effects on glucose metabolism and bone mineral density (BMD) after 1 year of rhIGF-1 therapy. Design and Patients: Three affected siblings, their heterozygous parents, and two healthy controls participated. The subjects received a dose of rhIGF-1, followed by serial blood samples collected over 24 hours. The two younger siblings were started on rhIGF-1 treatment. An oral glucose tolerance test and dual-energy X-ray absorptiometry scans were obtained at baseline and after 1 year of treatment. Results: Subcutaneous administration of rhIGF-1 increased the concentration of free and total IGF-1 in patients with PAPP-A2 deficiency. The PK profile was comparable in all participants. At baseline, all three subjects demonstrated insulin resistance and below-average BMD. Treatment with rhIGF-1 is ongoing in the youngest patient but was discontinued in his brother because of the development of pseudotumor cerebri. The treated patient had an increase in height velocity from 3.0 to 6.2 cm/y, resolution of insulin resistance, and an increase in total body BMD. Conclusions: rhIGF-1 at standard dosages resulted in similar PK characteristics in patients with PAPP-A2 deficiency, heterozygous relatives, and healthy controls. The youngest affected patient experienced a modest growth response to therapy with rhIGF-1, as well as beneficial effects on glucose metabolism and bone mass.