Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature.

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.

Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux.

Acromesomelic dysplasia are a heterogeneous group of disorders with variable spectrum and severity of skeletal anomalies in the affected individuals. Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. Several homozygous inactivating mutations in NPR2 have been identified in different AMDM patients. We report five novel variants in affected individuals in four different families. These include two nonsense and three missense variants. This study broadens the genotypic spectrum of NPR2 mutations in individuals with AMDM and also describes the intra- and inter-familial phenotypic variability due to NPR2 variants.

Maternal Predictors of Intrauterine Growth Retardation.

OBJECTIVE: To identify maternal factors associated with intrauterine growth restriction (IUGR). STUDY DESIGN: A case-control study. PLACE AND DURATION OF STUDY: Neonatal Unit of The Aga Khan Hospital for Women (AKHW), Karimabad, from January 2014 to December 2015. METHODOLOGY: Cases were IUGR live born babies (n=90), while control were appropriate-for-gestational age (AGA) babies (n=180). Information recorded in pre-designed proforma included gestational age and birth weight of baby, demographics of mothers, pregnancy related medical and obstetric complications. Data were analysed through SPSS-19. Multivariable logistic regression was used to determine the maternal factors associated with the intrauterine growth restriction. RESULTS: Maternal factors associated with IUGR after adjusting for confounders in the multivariable model included younger age (OR=0.9, CI=0.8-0.9), poor gestational weight gain (OR=3.0, CI=1.6-6.1) and history of previous abortion (OR=3.06, CI=1.1-8.0). Significant interaction was found between pregnancy-induced hypertension (PIH) and parity of mother, primary-para mother with PIH having an increased risk for IUGR babies (OR=10.1, CI=1.0-23.2). CONCLUSION: Young age, primigravida status, low gestational weight gain, previous history of abortion, PIH and GDM have strong association with IUGR; hence, special consideration is essential to overcome these issues in order to improve maternal and neonatal health.