Spondyloepimetaphyseal Dysplasia, Genevieve Type

A number sign (#) is used with this entry because of evidence that Genevieve-type spondyloepimetaphyseal dysplasia (SEMDG) is caused by homozygous or compound heterozygous mutation in the NANS gene (605202) on chromosome 9q22.

Description

Spondyloepiphyseal dysplasia of the Genevieve type (SEMDG) is characterized by infantile-onset severe developmental delay and skeletal dysplasia, including short stature, premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses (summary by van Karnebeek et al., 2016).

Clinical Features

Camera et al. (1993) reported 2 sisters with what the authors considered to be a form of sponastrime dysplasia (271510). The skeletal abnormalities were similar but there was milder spinal involvement, microcephaly, mental retardation, and a slightly different facial appearance (a more flat face with a larger nose).

Verloes et al. (1995) reported a 10-year-old Polish boy with sponastrime dysplasia, microcephaly, and severe mental retardation. They suggested that the disorder in patients with the additional feature of mental retardation be designated 'sponastrime dysplasia type 2.' However, Langer et al. (1996) reviewed reported patients with the sponastrime form of skeletal dysplasia and noted that the patients described by Camera et al. (1993) and Verloes et al. (1995) did not exhibit the pattern of radiologic abnormalities seen in sponastrime dysplasia. They concluded that the designation 'sponastrime type 2' was not optimal and would likely lead to confusion in the classification of the disorders.

Genevieve et al. (2005) described what they considered to be a novel autosomal recessive form of SEMD and mental retardation in 2 Pakistani sisters born to first-cousin parents. SEMD, severe mental retardation, microcephaly, ataxia, facial dysmorphism, and hirsutism of the back and legs were noted in both girls. Facial features included coarse facies, low anterior and posterior hairline, brachycephaly, simple and flat ears, synophrys, broad nose, and full lips with eversion of the lower lip. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones, and narrow iliac wings without lacy pelvis iliac crest. Clinical and radiologic features worsened as the disease progressed. Other investigations, including karyotype, plasma and urinary amino acids and organic acids, and blood and fibroblast lysosomal enzymes, were normal. Electron microscopy of the skin revealed an abnormally large number of small vacuoles along the cytoplasmic membrane and large vacuoles containing either myelinic or granular osmiophilic bodies. The authors suggested that the sisters may have had a metabolic disorder.

Van Karnebeek et al. (2016) studied 9 affected individuals from 6 families with global developmental delay, cognitive impairment, and skeletal dysplasia. Although body measurements at birth were normal or slightly lower than normal, growth velocity slowed during the first or second year of life and all adult patients exhibited short stature with shortening of both the trunk and limbs. Facial dysmorphism included prominent forehead, mild synophrys, sunken nasal bridge, prominent bulbous nasal tip, and full lips. The skeletal dysplasia was characterized by premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses. Other features included muscle hypotonia in infancy, with delays in early motor development such as sitting and walking. Seizures were a prominent and early feature in 1 patient, but were infrequent in some patients and absent in others. Neuroimaging was performed in 6 patients, 4 of whom showed moderate cerebral atrophy with nonspecific white matter changes; 1 patient showed prenatal-onset hydrocephalus, and 1 showed perisylvian microgyria, small basal ganglia, and reduced white matter mass.

Molecular Genetics

In 2 sisters from an Italian family with SEMDG, previously reported by Camera et al. (1993), and an affected brother and sister from an unrelated Italian family, all of whom were negative for mutation in the GNE gene (603824), van Karnebeek et al. (2016) performed exome sequencing and identified biallelic mutations in the NANS gene (605202), including a shared insertion/deletion (605202.0001) in all 4 patients, together with a frameshift mutation in the 2 sisters (605202.0002) and a splice site mutation (605202.0003) in the brother and sister. All 3 mutations segregated with disease in the families, and all resulted either in unstable or nonfunctional NANS mRNA, or in reduced levels of wildtype transcripts. Screening of the NANS gene in 4 more patients with SEMDG, including a Pakistani girl previously reported by Genevieve et al. (2005), identified biallelic mutations in all (see, e.g., 605202.0004-605202.0006). In addition, metabolic screening in an affected 4-year-old Dutch boy revealed an unusual metabolite, N-acetyl-D-mannosamine (ManNAc), in plasma and urine, and subsequent exome sequencing identified compound heterozygosity for missense mutations in the NANS gene (605202.0007-605202.0008); NANS was a prioritized candidate gene because ManNac6-phosphate is a substrate for the NANS enzyme. Analysis of patient fibroblasts confirmed functional impairment of NANS activity in the metabolic pathway of sialic acid biosynthesis and protein sialylation; van Karnebeek et al. (2016) suggested that NANS deficiency should be included as part of the congenital disorders of glycosylation (CDGs; see 212065).

Exclusion Studies

In 2 Pakistani sisters with a form of SEMD and mental retardation, Genevieve et al. (2005) excluded mutation in the DYM gene (607461), which is responsible for Dyggve-Melchior-Clausen syndrome (223800), and in the PAPSS2 gene (603005), which is responsible for the Pakistani type of SEMD (612847).