Background Central precocious puberty (CPP) has been associated with loss-of-function mutations in two paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic DNA was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404+8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (A and g.-223 G>A) in two girls with CPP However, both had normal DLK1 serum levels. Conclusion Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.

The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow‐up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) (51 benign HPA, 32 phenylketonuria, 4 DNAJC12 defect, and 2 primapterinuria), 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR‐1), 1 TYR‐3, 4 maple syrup urine disease (MSUD), 2 branched‐chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium‐chain acyl‐CoA dehydrogenase deficiency (MCADD), 13 very long‐chain acyl‐CoA dehydrogenase deficiency, 2 long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl‐coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT‐II) deficiency, 1 CPT‐I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA‐1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3‐methylcrotonyl‐CoA carboxylase, 1 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at newborn screening result (1 LCHADD, 5 PA, 1 CPT‐II deficiency, 1 MMA, 3 MMAHC, 2 MSUD, 2 OTC deficiency, 1 CTLN1, 1 MCADD, 2 TYR‐1). No false negative cases were identified. Genetic diagnosis was conclusive in all biochemically confirmed cases, except for two infants with HPA, identifying pathogenic variants in 32 different genes. The conditions with the highest incidence were HPA (1/6661) and MCAD deficiencies (1/13 787).

Background: LZTR1 participates in RAS protein degradation, hence limiting the RAS/MAPK cascade. Pathogenic mutations in LZTR1 (MIM:600574) have been described in a few patients with Noonan syndrome (NS). Three patients with LZTR1 mutations of different genetic transmission and NS phenotype are herein characterized. Clinical Cases: Case 1 is a 5-year-old boy with NS phenotype. Sanger sequencing of PTPN11 and SOS1 identified no mutations. Whole exome sequencing (WES) detected a heterozygous missense mutation in LZTR1:c.742G>A (p.Gly248Arg) (exon 8, Kelch 4 functional domain). Bioinformatic algorithms predict a deleterious effect of this variant, previously described to cause NS. Case 2 is a 4-year-old boy with NS phenotype. Direct sequencing of 8 genes associated with NS identified no mutations. WES localized a homozygous missense mutation in LZTR1:c.2074T>C (p.Phe692Leu, exon 18). This mutation has not been reported before and is predicted to have a deleterious effect on the protein. Case 3 is an 8-year-old boy who shares NS phenotype with his mother. A multigene panel for RASopathies showed a heterozygous missense variant in LZTR1:c.730T>C (p.Ser244Pro) (exon 8; Kelch 4 functional domain) that was maternally inherited. This variant has not been previously described; however, in silico predictors classify it as deleterious. Familial segregation suggests its pathogenicity. Conclusions: The molecular approach for syndromic phenotypes associated with various genes should involve complete/updated panels or WES rather than gene-by-gene sequencing. RASopathy genetic panels should incorporate LZTR1. Patients with pathogenic mutations in LZTR1 exhibit a characteristic NS gestalt but variable cardiac, height, and neurodevelopment expressions, with recessive inheritance possibly associating with a more severe phenotype.

Objectives: We present the results of our experience in the diagnosis and follow up of the positive cases for propionic, methylmalonic acidemias and cobalamin deficiencies (PA/MMA/MMAHC) since the Expanded Newborn Screening was implemented in Madrid Region. Methods: Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by MS/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. Results: In the period 2011–2020, 588,793 children were screened, being 953 of them were referred to clinical units for abnormal result (192 for elevated C3 levels). Among them, 88 were false positive cases, 85 maternal vitamin B12 deficiencies and 19 were confirmed to suffer an IEM (8 PA, 4 MMA, 7 MMAHC). Ten out 19 cases displayed symptoms before the NBS results (6 PA, 1 MMA, 3 MMAHC). C3, C16:1OH+C17 levels and C3/C2 and C3/Met ratios were higher in newborns with PA/MMA/MMAHC. Cases diagnosed with B12 deficiency had mean B12 levels of 187.6 ± 76.9 pg/mL and their mothers 213.7 ± 95.0; 5% of the mothers were vegetarian or had poor eating while 15% were diagnosed of pernicious anemia. Newborns and their mothers received treatment with B12 with different posology, normalizing their levels and the secondary alterations disappeared. Conclusions: Elevated C3 are a frequent cause for abnormal result in newborn screening with a high rate of false positive cases. Presymptomatic diagnosis of most of PA and some MMA/MMAHC is difficult. Vitamin B12 deficiency secondary to maternal deprivation is frequent with an heterogenous clinical and biochemical spectrum.