Mild phenotype in two siblings with a missense GHR variant

Objectives Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features. Case presentation In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS. Conclusion In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.

Silver Russell syndrome in a preterm girl with 8q12.1 deletion encompassing PLAG1.

Silver Russell syndrome (SRS) is a congenital disorder characterised by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases IGF2 expression and produces a Silver Russell syndrome like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS.

Novel Variant in PLAG1 in a Familial Case with Silver–Russell Syndrome Suspicion

Silver–Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver–Russell syndrome.

92 Postnatal growth retardation impairs intestinal mucosal barrier in piglets

The piglets with postnatal growth retardation (PGR) have high mortality and morbidity during their growth and development. Abnormal development of small intestine is casually implicated in impaired growth, but the exact mechanism still remains poorly understood. Thus, the present study investigated the immune profiles related to intestinal mucosal barrier in PGR and healthy piglets. The plasma sample, middle segments of small intestine, and the intestinal mucosa were obtained from healthy and PGR piglets at 42d of age. Compared to healthy piglets, higher plasma concentrations of diamine oxidase and D-lactate were observed in PGR piglets (P < 0.05). Decreased villous height, ratio of villous height to crypt depth, as well as sparse villi, jagged microvilli were also found in jejunum and ileum of PGR piglets. PGR also decreased the percentage of proliferating cell nuclear antigen (PCNA)-positive cells, as well as abundance of Zonula occludens-1, Occludin, Claudin-1, and E-cadherin mRNA and protein in jejunal and ileal mucosa (P < 0.05). The lower concentration of sIgA in jejunal mucosa, and lysozyme in both jejunal and ileal mucosa, but higher level of β-defensins in the ileal mucosa were observed in PGR piglets as compared to healthy piglets (P < 0.05). The percentage of CD68-positive cells were significantly increased, but the levels of P-glycoprotein were decreased in jejunum and ileum from PGR piglets (P < 0.01). Moreover, the expression of proteins involved in p38 MAPK/NF-kB pathway was significantly upregulated in jejunal and ileal mucosa from PGR piglets (P < 0.05). Collectively, these results indicated that the PGR piglets exhibited impaired intestinal integrity, and decreased capacity of mucosal immune function, which may result in severe inflammatory response via the activation of p38 MAPK/NF-kB pathway. Our findings may have important implications in the prevention and treatment of the intestinal mucosal barrier dysfunction in piglets.

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.