Microcephaly, Short Stature, and Polymicrogyria with or without Seizures

Alternative Names

  • MSSP
  • Polymicrogyria with Seizures
  • PMGYS

Associated Genes

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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations of the nervous system

OMIM Number

614833

Mode of Inheritance

Autosomal recessive

Gene Map Locus

18q22.2

Description

MSSP is a rare congenital disorder that has so far been reported in only a handful of families worldwide.  It is characterized by microcephaly, primordial dwarfism, polymicrogyria and intrauterine growth retardation.  Patients also tend to suffer from severe intellectual disability, delayed motor development, delayed speech development and microcephaly related craniofacial dysmorphism.  Brain MRIs of affected patients may reveal several abnormal findings such as simplified gyration, areas of lissencephaly or pachygyria, dysgenesis or agenesis of the corpus callosum, periventricular heterotopia of grey matter and a deformed ventricular system.

MSSP patients require life-long treatment and support.  Treatment is focused on symptoms and may include physical therapy, speech therapy and educational aids.  Anti-epileptic medications are administered in the case of seizures.

Molecular Genetics

The syndrome follows an autosomal recessive pattern of inheritance and is caused by homozygous or compound heterozygous mutations in the RTTN gene.  While the specific function of RTTN is unknown, it is predicted to play a role in early developmental processes such as axial rotation and left-right specification.  Mutations that have been associated with MSSP include several transversions and transitions resulting in amino acid substitutions at highly conserved residues and an insertion (c.2885+8A-G) resulting in a premature stop codon (S963X).  

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Shamseldin et al. (2015) described two Arab families with MSSP affected individuals.  Family 1 was a Yemeni consanguineous family with three affected siblings. The index patient, aged 12 years, showed severe short stature, microcephaly and craniofacial dysmorphism.  Brain scans revealed few sulcations and bilateral pachygyria.  He also had a single kidney and bilateral hearing loss.  Milestones were delayed and he lacked speech.  His two younger brothers also suffered from microcephaly, short stature and intellectual disability.  They were both found to have sacral lesions cephalad to the gluteal crease.  In family 2, a 5.5-year-old Saudi Arabian boy, born to healthy consanguineous parents, was found to suffer from severe microcephaly with simple gyration, microcephalic dwarfism, and craniofacial dysmorphism.  He was born at 34 weeks due to severe intrauterine growth retardation.  He had mildly delayed motor development while speech and cognitive development were severely limited. Autozygome analysis and linkage analysis of the two families revealed the association of RTTN with this disorder. 

Yemen

See: Saudi Arabia > Shamseldin et al., 2015

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