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

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.

Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders

“…The present cohort (15 unrelated families, 14 of them with NLS and one with a very severe form of PSAT1 deficiency) increases the number of molecularly characterized unrelated families affected by NLS to a total of 35 (Acuna‐Hidalgo et al, 2014; Bourque et al, 2019; El‐Hattab et al, 2016; Mattos et al, 2015; Shaheen et al, 2014), among which a PSAT1 defect turned out to be the most common cause (accounting for 18 out of 35 unrelated cases; 51%), closely followed by PHGDH (16/35; 46%). This distribution may be affected by population selection, as in the present and previously published NLS cases, origin from the Middle East has been dominant with at least one obvious PSAT1 founder allele, c.296C>T, p.(Ala99Val).…”

“…The phenotype ranges from nonspecific developmental delay (Tabatabaie et al, 2011) to the severe lethal disease known as Neu–Laxova syndrome (NLS; MIM# 256520). Following the first descriptions by Neu and Laxova in 1971 and 1972, respectively (Laxova, Ohara, & Timothy, 1972; Neu, Kajii, Gardner, & Nagyfy, 1971), fewer than 100 cases of NLS have been reported to date (Acuna‐Hidalgo et al, 2014; Bourque et al, 2019; Cavole et al, 2020; Coto‐Puckett et al, 2010; El‐Hattab et al, 2016; Manning, Cunniff, Colby, El‐Sayed, & Hoyme, 2004; Mattos et al, 2015; Ni et al, 2019; Shaheen et al, 2014). The clinical hallmarks of this disorder are severe intrauterine growth restriction (IUGR), microcephaly, cutaneous abnormalities, and distinctive craniofacial features including sloping forehead, ocular hypertelorism, prominent eyes, ectropion, flat nose, round gaping mouth, micrognathia, short neck, and low‐set malformed ears.…”

Neuropathology of genetically defined malformations of cortical development—A systematic literature review

“…On histological preparations, the cortex was described as having a simplified gyral pattern for CRADD , and as normal for ACTB and PHGDH (Table 1 ). However, the three publications describing these genes did not provide images of the cortical features for correlation [ 28 , 29 , 30 ]. Nevertheless, an ACTB variant has been described in a patient with neurodegeneration, iron accumulation in pallidal and nigral neurons as well as rod‐like eosinophilic structures in the neocortex, which are distinctive and findings and could possibly form a diagnostic clue [ 28 ].…”

“…On histological preparations, the cortex was described as having a simplified gyral pattern for CRADD, and as normal for ACTB and PHGDH (Table 1). However, the three publications describing these genes did not provide images of the cortical features for correlation [28][29][30].…”

Clinical, molecular, and pathological findings in a Neu–Laxova syndrome stillborn: A Brazilian case report

“…Phenotypic variability in the central nervous system has been documented in patients with NLS (Coto‐Puckett et al, ). Cerebellar hypoplasia has not been typically reported in NLS cases (Bourque et al, ). Our case presented lissencephaly, corpus callosum agenesis, asymmetric enlargement of lateral ventricles, hematoma of choroid plexus, and cerebellar hypoplasia.…”