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FG syndrome

ORPHA323
Synonym(s) Keller syndrome
Prevalence >1 / 1000
Inheritance X-linked recessive
Age of onset Childhood
ICD-10
  • Q87.8
OMIM
UMLS
  • C0220769
MeSH
  • C537923
MedDRA -

Summary

FG syndrome (FGS) is a multiple congenital anomalies (MCA) and developmental delay syndrome with a characteristic psychological pattern. The condition is common; prevalence is estimated at a minimum of 1/500. Males are affected, but carrier girls and women may also be affected, sometimes more severely than the males. Patients present with a wide range of manifestations which extensively overlap those of the GBBB (Opitz) syndrome (see this term). Typical manifestations include relative shortness compared to head size, congenital hypotonia with delayed motor and speech development. Uncommon anomalies include cleft palate, laryngeal cleft, squint, hernia, hypospadias, hydrocele, sleep apnea, gastroesophageal involvement, sensorineural deafness, recurrent otitis, reflux, constipation, delayed development of sensory integration, attention deficit disorder, self-absorption and fascinations with mechanical toys and objects. Gross malformations may include agenesis of corpus callosum, Chiari I malformation, congenital heart defects, intestinal atresias and limb defects. FGS is an incompletely recessive X-linked disorder. Mutations in the MED12 gene (Xq13) cause FGS1, the so-called Opitz-Kaveggia syndrome which has a characteristic phenotype. Mutations in the FLNA (Xq28.2; FGS2) (leading to typical periventricular nodular heterotopia on MRI), CASK (Xp11.4; FGS4), UPF3B (Xq25-26; FGS6), and BRWD3 (Xq21.1; FGS7) genes have also been identified. Two other loci have so far been mapped to the X chromosome: Xp22.22 (FGS3) and Xq22.3 (FGS5). A candidate gene for FGS3 is MID1. Diagnosis is based on family history, pre- and postnatal events, history of growth development, psychological phenotype, physical and radiographic findings, and genetic tests. Differential diagnoses include mild cases of GBBB syndrome, Atkin-Flaitz syndrome, fragile X syndrome, Keipert syndrome, nasodigitoacoustic syndrome, Say-Meyer syndrome, Donnai-Barrow syndrome, Sotos syndrome, Pelizaeus-Merzbacher disease, C syndrome, Dubowitz syndrome, and Renpenning syndrome (see these terms). Prenatal diagnosis may be suspected by ultrasonography (or MRI) revealing large head, dilated ventricles, corpus callosum dysgenesis, cleft palate, and/or hypospadias. Molecular analysis of MED12, FLNA, BRWD3, and UPF3B from chorionic villus samples is possible. Genetic counseling may be difficult since there seems to be a transmission ratio distortion (TRD) in FGS. In this case, TRD refers to the greater than 50% theoretical risk for a carrier mother to have affected sons and carrier/affected daughters. Management is symptomatic. Surgery may be required for cleft palate, laryngeal cleft, reflux, feeding tube, hernia, squint, hypospadias, hydrocele, Chirai I malformation, and tethered spinal cord. Obstructive sleep apnea may require constant positive airway pressure (CPAP). Cochlear implant may be needed in case of profound sensorineural hearing loss. Recurrent otitis may require pressure equalization tubes. If there is delayed bone age, severe growth failure with evidence of pituitary dysgenesis, growth hormone treatment may be indicated. All children with FGS require an individualized educational plan. Psychological guidance is advised in all cases. True intellectual deficit and autism are rare and, in most cases, a cautiously optimistic outlook may be offered. Slow and gradual improvement over time is the rule, not the exception.

Expert reviewer(s)

  • Pr John M OPITZ

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