Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , LDL-Colesterol/sangue , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Pró-Proteína Convertase 1/antagonistas & inibidores , Adulto , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/efeitos dos fármacos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 1/sangue , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Issue: To report a homozygous pathogenic variant in PCSK1 in a boy affected with proprotein convertase 1/3 (PC1/3) deficiency. Case Description and Literature Review: A male infant born to consanguineous Turkish parents presented in the first week of life with transient central diabetes insipidus, watery diarrhea, micropenis due to hypogonadotropic hypogonadism and GH deficiency, and transient asymptomatic hypoglycemia. Further endocrine defects gradually appeared, including central hypothyroidism and mild central hypocortisolism (at 1 year), central diabetes insipidus that reappeared progressively (at 2.5 years), and obesity (at 2 years). Whole-exome sequencing revealed a homozygous nonsense pathogenic variant (NM_000439.4) c. 595 C>T in exon 5 of PCSK1, not yet reported in cases of PC1/3 deficiency. To date, 26 cases of PC1/3 deficiency have been reported in the literature. All individuals had early and severe malabsorptive diarrhea and 83% had polyuria-polydipsia syndrome (before 5 years). Most (79%) had early onset obesity. Various endocrine disorders were present, including GH deficiency (44%), mild central hypothyroidism (56%), central hypogonadism (44%), central hypocortisolism (57%), and postprandial hypoglycemia (52%). When described (n = 15), proinsulin levels were consistently high: between 8 and 154 times the upper limit of normal (mean 74). Conclusion: We described a homozygous nonsense pathogenic variant (NM_000439.4) c. 595 C>T in exon 5 of PCSK1 in a boy with congenital PC1/3 deficiency. Elevated proinsulin could be useful in the diagnosis of this condition.
Assuntos
Doenças do Sistema Endócrino/genética , Obesidade/genética , Proinsulina/sangue , Pró-Proteína Convertase 1/deficiência , Doenças Raras/genética , Pré-Escolar , Códon sem Sentido , Consanguinidade , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/diagnóstico , Éxons/genética , Homozigoto , Humanos , Masculino , Mutação , Obesidade/sangue , Obesidade/diagnóstico , Pró-Proteína Convertase 1/sangue , Pró-Proteína Convertase 1/genética , Doenças Raras/sangue , Doenças Raras/diagnóstico , TurquiaRESUMO
Leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, melanocortin-4 receptor, melanocortin-3 receptor, brain-derived neurothrophic factor, neurotrophic tyrosine receptor kinase type 2, and single minded 1 genes, which are the genes that have been shown to cause monogenic obesity, are related to the leptin-melanocortin system. Congenital prohormone convertase 1 deficiency is a very rare syndrome characterized by early-onset obesity, small intestinal dysfunction, impaired glucose homeostasis, and disrupted prohormone processing. Obesity phenotype seen in this syndrome is known to be due to reduced melanocortin signaling in the hypothalamus which arises as a result of impaired processing of proopiomelanocortin. However, prohormone convertase 1 cleaves a number of other neuropeptides involved in feeding behavior and impaired cleavage of these neuropeptides, particularly NUCB2/nesfatin, may be a contributing factor for development of obesity in these cases. Until now, in prohormone convertase 1 deficient patients, low serum nesfatin-1 levels have not been mentioned to be a possible cause of obesity, we suggest that in these patients low levels of anorexigenic peptid nesfatin-1 might be another facilitating factor for development of obesity.
