Lucie Pépin1, Estelle Colin2,3, Marine Tessarech2,3, Stéphanie Rouleau1, Natacha Bouhours-Nouet1,4, Dominique Bonneau2,3, Régis Coutant1,4. 1. Department of Pediatric Endocrinology and Diabetology, University Hospital of Angers, Angers Cedex 9, France. 2. Department of Biochemistry and Genetics, University Hospital of Angers, Angers Cedex 9, France. 3. UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, Angers Cedex 9, France. 4. Reference Center for Rare Diseases of Pituitary Origin-Constituent Site (HYPO), University Hospital of Angers, Angers Cedex 9, France.
Abstract
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.
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.
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