microcephaly hiatal hernia and nephrotic syndrome

Galloway-Mowat Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia, hypertelorism, epicanthal folds and ptosis are prominent ocular features.  Other manifestations include corneal opacities, cataracts, and optic atrophy.  Nystagmus of a roving nature is seen in all individuals and is usually present at birth.  There is evidence of visual impairment in more than 90% of individuals.  Features of an anterior chamber dysgenesis such as a hypoplastic iris are sometimes present.

The ocular features of this syndrome have not been fully described.

Systemic Features: 

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.

Genetics

Gallaway-Mowat syndrome is likely a spectrum of disease.  Homozygous mutations in the WDR73 gene (15q25) are responsible for one form of this syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for GAMOS.

References
Article Title: 

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73

Jinks RN, Puffenberger EG, Baple E, Harding B, Crino P, Fogo AB, Wenger O, Xin B, Koehler AE, McGlincy MH, Provencher MM, Smith JD, Tran L, Al Turki S, Chioza BA, Cross H, Harlalka GV, Hurles ME, Maroofian R, Heaps AD, Morton MC, Stempak L, Hildebrandt F, Sadowski CE, Zaritsky J, Campellone K, Morton DH, Wang H, Crosby A, Strauss KA. Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73. Brain. 2015 Aug;138(Pt 8):2173-90.  PubMed PMID: 26070982.

PubMed ID: 
26070982

Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C, Boyer O, Daniel L, Gubler MC, Ekinci Z, Tsimaratos M, Chabrol B, Boddaert N, Verloes A, Chevrollier A, Gueguen N, Desquiret-Dumas V, Ferre M, Procaccio V, Richard L, Funalot B, Moncla A, Bonneau D, Antignac C. Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. Am J Hum Genet. 2014 Dec 4;95(6):637-48..

PubMed ID: 
25466283
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