RESUMEN
Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.
Asunto(s)
Raquitismo Hipofosfatémico Familiar , Hipofosfatemia , Humanos , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/diagnóstico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Hipercalciuria/diagnóstico , Hipercalciuria/tratamiento farmacológico , Hipercalciuria/genética , Riñón/metabolismo , Fosfatos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismoRESUMEN
BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
Asunto(s)
Enfermedades Raras , Enfermedades no Diagnosticadas , Estados Unidos , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Atención Terciaria de Salud , Medicina Genómica , Pruebas Genéticas , Asesoramiento GenéticoRESUMEN
BACKGROUND: We sought to evaluate the association between vitamin D deficiency and the severity of coronavirus disease 2019 (COVID-19) infection. METHODS: Multiple databases from 1 January 2019 to 3 December 2020 were searched for observational studies evaluating the association between vitamin D deficiency and severity of COVID-19 infection. Independent reviewers selected studies and extracted data for the review. The main outcomes of interest were mortality, hospital admission, length of hospital stay and intensive care unit admission. RESULTS: Seventeen observational studies with 2756 patients were included in the analyses. Vitamin D deficiency was associated with significantly higher mortality (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.50-4.05; 12 studies; hazard ratio [HR]: 4.11, 95% CI: 2.40-7.04; 3 studies), higher rates of hospital admissions (OR: 2.18, 95% CI: 1.48-3.21; 3 studies) and longer hospital stays (0.52 days; 95% CI: 0.25-0.80; 2 studies) as compared to nonvitamin D deficient status. Subgroup analyses based on different cut-offs for defining vitamin D deficiency, study geographic locations and latitude also showed similar trends. CONCLUSIONS: Vitamin D deficiency is associated with greater severity of COVID-19 infection. Further studies are warranted to determine if vitamin D supplementation can decrease the severity of COVID-19.
Asunto(s)
COVID-19 , Deficiencia de Vitamina D , Humanos , Unidades de Cuidados Intensivos , SARS-CoV-2 , Vitamina D , Deficiencia de Vitamina D/complicacionesRESUMEN
Phosphate plays a critical and diverse role in human physiology. In addition to its importance in skeletal mineralization, it is essential for energy homeostasis, enzyme function, and cell membrane integrity. These diverse functions of phosphate provide an explanation for the range of symptoms and clinical manifestations observed in patients with both acute and chronic causes of hypophosphatemia. Normal phosphate homeostasis involves several major systems, including the gastrointestinal tract, bones, and kidneys. Phosphate balance is maintained directly and indirectly by 1α,25-dihydroxyvitamin D3, parathyroid hormone, and the osteocyte-derived phosphatonin fibroblast growth factor 23. This review discusses normal phosphate homeostasis, the clinical manifestations and causes of hypophosphatemia, and an approach to establish a diagnosis and appropriate management.
Asunto(s)
Hipofosfatemia , Osteomalacia , Huesos/metabolismo , Factores de Crecimiento de Fibroblastos , Humanos , Hipofosfatemia/diagnóstico , Hipofosfatemia/etiología , Hipofosfatemia/terapia , Osteomalacia/diagnóstico , Osteomalacia/etiología , Osteomalacia/terapia , Hormona Paratiroidea , Fosfatos/metabolismoRESUMEN
Branchio-oto-renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.
Asunto(s)
Síndrome Branquio Oto Renal/diagnóstico , Hormona del Crecimiento/genética , Proteínas de Homeodominio/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas/genética , Síndrome Branquio Oto Renal/diagnóstico por imagen , Síndrome Branquio Oto Renal/genética , Síndrome Branquio Oto Renal/patología , Femenino , Hormona del Crecimiento/deficiencia , Humanos , Lactante , Hipófisis/metabolismo , Hipófisis/patología , Adenohipófisis/diagnóstico por imagen , Adenohipófisis/metabolismo , Adenohipófisis/patologíaRESUMEN
BACKGROUND: (+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA). METHODS: This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. RESULTS: Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events. CONCLUSION: (+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. SYNOPSIS: A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin.
Asunto(s)
Antioxidantes/administración & dosificación , Catequina/administración & dosificación , Ataxia de Friedreich/tratamiento farmacológico , Corazón/diagnóstico por imagen , Adolescente , Niño , Ecocardiografía , Femenino , Ataxia de Friedreich/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , CaminataRESUMEN
Prader-Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11-q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader-Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15-related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co-occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15-related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.
Asunto(s)
Síndrome de Angelman/genética , Ictiosis/genética , Síndrome de Prader-Willi/genética , Esfingosina N-Aciltransferasa/genética , Adolescente , Adulto , Síndrome de Angelman/patología , Niño , Preescolar , Cromosomas Humanos Par 15/genética , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/genética , Anomalías Congénitas/patología , Femenino , Genes Recesivos/genética , Impresión Genómica/genética , Humanos , Ictiosis/complicaciones , Ictiosis/patología , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Herencia Materna/genética , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/patología , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Disomía Uniparental/patología , Adulto JovenRESUMEN
Dual-energy X-ray absorptiometry (DXA) is widely used in the evaluation of bone fragility in children. Previous recommendations emphasized total body less head and lumbar spine DXA scans for clinical bone health assessment. However, these scan sites may not be possible or optimal for all groups of children with conditions that threaten bone health. The utility of DXA scans of the proximal femur, forearm, and radius were evaluated for adequacy of reference data, precision, ability of predict fracture, and applicability to all, or select groups of children. In addition, the strengths and limitations of vertebral fracture assessment by DXA were evaluated. The new Pediatric Positions provide guidelines on the use of these additional measures in the assessment of skeletal health in children.
Asunto(s)
Absorciometría de Fotón/normas , Densidad Ósea , Fémur/diagnóstico por imagen , Antebrazo/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Osteoporosis/diagnóstico , Fracturas de la Columna Vertebral/diagnóstico , Niño , Conferencias de Consenso como Asunto , Humanos , Osteoporosis/complicaciones , Fracturas de la Columna Vertebral/etiologíaRESUMEN
BACKGROUND: There is a lack of consensus on the cardiometabolic consequences of mild subclinical hypothyroidism (SCH) among children. The objective of the current study was to compare lipid profiles in children with mild SCH with those of euthyroid children. STUDY DESIGN: Retrospective medical record review. PATIENTS: Children (ages 2-18 years) who had undergone simultaneous measurement of TSH, free thyroxine (T4) and lipids. Lipids in children with mild SCH (TSH 5-<10 mIU/L and normal free T4, n = 228) were compared with those in euthyroid children (n = 1215). RESULTS: TSH level was positively associated with total cholesterol and nonhigh density lipoprotein (non-HDL) cholesterol [ß 0.05(0.03-0.08), P < .0001 and ß 0.05(0.03-0.08), P < .0001, respectively]. Total cholesterol was significantly higher in children and adolescents with mild SCH compared with euthyroid children (4.43 ± 1.14 mmol/L vs 4.2 ± 0.85 mmol/L, P = .0005). Similarly, non-HDL cholesterol level was also higher in children with mild SCH relative to euthyroid children (3.08 ± 1.14 mmol/L vs 2.91 ± 0.8 mmol/L, P = .001). The adjusted odds ratio of having elevated total cholesterol and elevated non-HDL cholesterol was greater in children with mild SCH compared with euthyroid children (OR 1.88, 95% CI; 1.28-2.73; P = .001 and 1.72, 95% CI 1.2-2.5; P = .003, respectively). The presence of thyroid autoimmunity was not associated with higher rates of dyslipidaemia. CONCLUSIONS: Mild SCH in children and adolescents was associated with higher rates of elevated total cholesterol and elevated non-HDL cholesterol. Randomized placebo controlled studies are warranted to determine if treatment of mild SCH in children leads to improvement in lipid profile.
Asunto(s)
Dislipidemias/sangre , Dislipidemias/complicaciones , Hipotiroidismo/sangre , Hipotiroidismo/etiología , Adolescente , Niño , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Masculino , Estudios Retrospectivos , Pruebas de Función de la Tiroides , Tirotropina/sangreRESUMEN
OBJECTIVES: Plant-based milk alternatives are increasingly utilized in children with cow milk allergy, lactose intolerance, and personal preference. However, notable differences exist in mineral content between cow milk and plant-based alternatives. Almond milk, in particular, varies in mineral and caloric content across different brands. This case report highlights a toddler who developed hypercalcemia and hypophosphatemia attributed to almond milk consumption. CASE PRESENTATION: A fourteen-month-old girl with a history of biliary atresia underwent liver transplant at seven months of age. She was exclusively consuming almond milk for two months prior to presentation. She was admitted to the hospital for severe hypercalcemia (14.6 mg/dL) and hypophosphatemia (1.6 mg/dL). She had elevated random urine calcium to creatinine ratio (2.56 mg/g) and low urine phosphorus to creatinine ratio (<0.44 mg/g) were noted. Parathyroid hormone (PTH) level was appropriately suppressed (<6 pg/mL), while 1,25 dihydroxyvitamin D level was slightly elevated at 88 pg/mL. Initial management included intravenous fluids, followed by a switch to a formula with higher phosphorus and lower calcium concentrations. The patient was discharged after six days with normalized calcium and phosphorus levels, which remained within the normal range. CONCLUSIONS: Although plant-derived milk serves as a viable alternative to cow milk, careful consideration of mineral content, particularly in infants and toddlers, is imperative. Sole reliance on almond milk for nutritional needs in this population is not recommended. Caregivers should be informed about the potential risks associated with almond milk consumption in infants and toddlers.
Asunto(s)
Hipercalcemia , Hipofosfatemia , Prunus dulcis , Lactante , Animales , Femenino , Bovinos , Humanos , Hipercalcemia/etiología , Calcio , Prunus dulcis/efectos adversos , Creatinina , Hipofosfatemia/etiología , Hormona Paratiroidea , Fósforo , Minerales , Calcio de la DietaRESUMEN
Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH)-mediated hypercalcemia seen in granulomatous disease, malignancy (most often lymphoma), or genetic mutations. Therapeutic options are limited. We report the case of a 67-year-old White man with nonmalignant, nongranulomatous, 1,25(OH)2D-mediated hypercalcemia treated successfully with cinacalcet. At presentation, he had hypercalcemia, hypercalciuria with recurrent nephrolithiasis, low PTH, elevated 1,25(OH)2D, and normal 25-hydroxyvitamin D. The 1,25(OH)2D levels were inappropriate in the setting of hypercalcemia with low PTH. Evaluations for sarcoidosis, tuberculosis, and malignancy were negative. Genetic testing showed biallelic variants in the CYP24A1 gene. Cinacalcet was trialed and showed normalization of calcium levels. On cinacalcet, biochemical indices showed a slight increase in 1,25(OH)2D and 24-hour urine calcium and mild decrease in PTH. He briefly experienced symptomatic hypocalcemia that resolved after reducing cinacalcet dose. Due to limited symptomatic benefit, he opted to stop cinacalcet. Additional follow-up showed intermittently elevated serum calcium levels after stopping cinacalcet, most recently 10.3â mg/dL. Cinacalcet may be a therapeutic option in nonmalignant, 1,25(OH)2D-mediated hypercalcemia. Further study is necessary to confirm efficacy, understand risks and benefits, and elucidate mechanism(s) of action.
RESUMEN
BACKGROUND: Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism. METHODS: We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [Asunto(s)
Hiperparatiroidismo Primario
, Hipoparatiroidismo
, Neoplasia Endocrina Múltiple Tipo 1
, Humanos
, Adulto
, Neoplasia Endocrina Múltiple Tipo 1/complicaciones
, Neoplasia Endocrina Múltiple Tipo 1/genética
, Neoplasia Endocrina Múltiple Tipo 1/cirugía
, Hiperparatiroidismo Primario/genética
, Hiperparatiroidismo Primario/cirugía
, Hiperparatiroidismo Primario/epidemiología
, Recurrencia Local de Neoplasia/cirugía
, Paratiroidectomía/efectos adversos
, Hipoparatiroidismo/etiología
, Genotipo
RESUMEN
BACKGROUND: Primary Hyperparathyroidism (PHPT) is rare in pediatric patients. Data regarding surgical outcomes are scarce. METHODS: Single-center retrospective review (1994-2020) of patients ≤21 years undergoing surgery for PHPT. RESULTS: 66 patients were identified (61% female, 17 ± 3 years). 71% of patients were symptomatic at diagnosis. 32% of patients had known familial syndromes, most commonly MEN-1. 23% of patients without a known mutation had genetic testing, 22% positive. 56% of the total and 19% of the familial cohort underwent focused exploration. Single gland disease was found in 19% of familial vs 85% of sporadic cases, p < 0.00001. Persistence was 9%, all in the sporadic group, p = 0.11. Recurrence was 15%: 38% in the familial vs 2% in the sporadic groups, p=0.0004. Time to recurrence was 59 months (Q1-38, Q3-95), familial 61 vs 124 months sporadic, p=0.001. CONCLUSION: Pediatric PHPT is frequently sporadic, although 5% of apparent sporadic cases are secondary to syndromes. Familial cases have higher rates of recurrence, requiring closer follow-up.
Asunto(s)
Hiperparatiroidismo Primario , Neoplasia Endocrina Múltiple Tipo 1 , Patología Quirúrgica , Humanos , Femenino , Niño , Masculino , Hiperparatiroidismo Primario/genética , Hiperparatiroidismo Primario/cirugía , Síndrome , Paratiroidectomía/efectos adversos , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Estudios RetrospectivosRESUMEN
The kidney is essential for the maintenance of normal calcium and phosphorus homeostasis. Calcium and inorganic phosphorus are filtered at the glomerulus, and are reabsorbed from tubular segments by transporters and channels which are regulated by 1α,25-dihydroxyvitamin (1α,25(OH)(2)D) and parathyroid hormone (PTH). The kidney is the major site of the synthesis of 1α,25(OH)(2)D under physiologic conditions, and is one of the sites of 24,25-dihydroxyvitamin D (24,25(OH)(2)D) synthesis. The activity of the 25(OH)D-1α-hydroxylase, the mixed function oxidase responsible for the synthesis of 1α,25(OH)(2)D, is regulated by PTH, 1α,25(OH)(2)D, fibroblast growth factor 23 (FGF23), inorganic phosphorus and other growth factors. Additionally, the vitamin D receptor which binds to, and mediates the activity of 1α,25(OH)(2)D, is widely distributed in the kidney. Thus, the kidney, by regulating multiple transport and synthetic processes is indispensible in the maintenance of mineral homeostasis in physiological states.
Asunto(s)
Riñón/metabolismo , Vitamina D/metabolismo , Absorción , Animales , Calcio/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Humanos , Riñón/enzimología , Fósforo/metabolismoRESUMEN
Congenital nephrotic syndrome (CNS) is a complex condition that requires multidisciplinary care. Hyperlipidemia is a characteristic feature with elevation of serum cholesterol and triglycerides. Little evidence is available to guide treatment of dyslipidemia in infants with CNS. We describe successful treatment of severe hypertriglyceridemia through dietary changes in a boy with CNS. A 9-day-old boy presented to the emergency department with lower extremity edema caused by deep venous thrombosis. Laboratory evaluation identified hypoalbuminemia, nephrotic-range proteinuria, and a pathogenic variant of the NPHS1 gene. The initial triglyceride concentration of 369 mg/dl increased to 3096 mg/dl by 5 weeks of age, when his diet consisted of breast milk. Refrigerated breast milk was skimmed by removing the top layer after allowing it to separate for 24 h. This process was repeated prior to use. Skimmed breast milk was supplemented with medium-chain triglyceride oil and an infant protein powder. After 2 days, the triglyceride concentration declined to 481 mg/dl and, by day 10, to 148 mg/dl. When breast milk supply decreased, a 1:1 ratio of skimmed maternal breast milk to an elemental, very low-fat formula was utilized. The triglyceride concentration remained below 400 mg/dl for the first year of life, except when skimmed breast milk was not available during hospitalization. Severe hypertriglyceridemia caused by CNS can present in the neonatal period and be difficult to manage. In our patient, skimmed maternal breast milk was successful in reducing the triglyceride concentration and should be considered a therapeutic option for children with hyperlipidemia caused by CNS.
Asunto(s)
Hiperlipidemias , Hipertrigliceridemia , Síndrome Nefrótico , Niño , Femenino , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/terapia , Lactante , Recién Nacido , Masculino , Leche Humana , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/genética , Síndrome Nefrótico/terapia , TriglicéridosRESUMEN
CONTEXT: Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications. OBJECTIVE: This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally. METHODS: Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised. RESULTS: The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time. CONCLUSION: Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.
Asunto(s)
Herencia Materna , Hormona Paratiroidea/sangre , Seudohipoparatiroidismo/diagnóstico , Sintaxina 16/genética , Calcio/sangre , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Eliminación de Gen , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Masculino , Estudios Prospectivos , Seudohipoparatiroidismo/sangre , Seudohipoparatiroidismo/genética , Índice de Severidad de la Enfermedad , SeudohipoparatiroidismoRESUMEN
CONTEXT: Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. OBJECTIVE: Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. DESIGN: Retrospective analysis. RESULTS: Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. CONCLUSION: Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.
Asunto(s)
Cromograninas , Seudohipoparatiroidismo , Cromograninas/genética , Metilación de ADN , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Humanos , Masculino , Oogénesis , Seudohipoparatiroidismo/genética , Estudios Retrospectivos , SeudohipoparatiroidismoRESUMEN
Rationale & Objective: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare monogenic disorder caused by SLC34A3 pathogenic variants. HHRH is characterized by kidney phosphate wasting, hypophosphatemia, hypercalciuria, an elevated 1,25-dihydroxyvitamin D level, nephrocalcinosis, and urinary stone disease. Previously, we reported a 100% prevalence of kidney cysts in the related CYP24A1 deficiency. Thus, in the current study, we characterized cysts' presence in HHRH, another monogenic cause of hypercalciuria, nephrocalcinosis, and urinary stone disease. Study Design: Case series. Setting & Participants: Medical records from the Mayo Clinic and the Rare Kidney Stone Consortium monogenic stone disease database were queried for patients with a genetically confirmed HHRH diagnosis. The number, sizes, and locations of kidney cysts in each patient were recorded. Results: Twelve patients with SLC34A3 pathogenic variants were identified (7 monoallelic, 5 biallelic). Of these, 5 (42%) were males, and the median (Q1, Q3) ages were 16 years (13, 35 years) at clinical presentation and 42 years (20, 57 years) at genetic confirmation. Kidney cysts were present in 9 of 12 (75%) patients, and the median (Q1, Q3) age at first cyst detection was 41 years (13, 50 years). The median number of cysts per patient was 2.0 (0.5, 3.5). Fifty percent of adult patients had a cyst number that exceeded the 97.5th percentile of an age- and sex-matched control population. All children had at least 2 or more total cysts. None had a family history of cystic kidney disease. Limitations: Retrospective study, possible selection bias, single-center experience. Conclusions: A strong association between HHRH and kidney cysts was observed. Similarities in the biochemical profiles of HHRH and CYP24A1 deficiency suggest elevated active vitamin D and hypercalciuria may be potential cystogenic factors. Further studies are needed to understand how genetic changes in SLC34A3 favor cyst formation.