Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis

Am J Med Genet A. 2019 May;179(5):813-816. doi: 10.1002/ajmg.a.61076. Epub 2019 Mar 5.

Abstract

Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.

Keywords: PHGDH; Neu-Laxova syndrome; cystic hygroma; exome sequencing; nuchal translucency.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / genetics*
  • Autopsy
  • Biopsy
  • Brain Diseases / diagnosis*
  • Brain Diseases / genetics*
  • Exome Sequencing
  • Fetal Growth Retardation / diagnosis*
  • Fetal Growth Retardation / genetics*
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Humans
  • Ichthyosis / diagnosis*
  • Ichthyosis / genetics*
  • Limb Deformities, Congenital / diagnosis*
  • Limb Deformities, Congenital / genetics*
  • Lymphangioma, Cystic / diagnosis*
  • Lymphangioma, Cystic / genetics*
  • Microcephaly / diagnosis*
  • Microcephaly / genetics*
  • Nuchal Translucency Measurement*
  • Sequence Analysis, DNA

Supplementary concepts

  • Neu Laxova syndrome