Research Update from Dr. Opitz

Research Update from Dr. John Opitz


Dr. John Opitz with Ben Wharton

Dear Friends of FG Syndrome,

In July of 2014, we received the following FGS3 research update from Dr. John Opitz, who asked us to share it with FG families.

Best wishes,
The FG Syndrome Family Alliance


July 16, 2014

Dear Friends, Parents, and Co-workers,

I must express once more my gratitude for your generous grant of $11,000 and for your incredible patience in awaiting results.  I am still receiving consultations nationally and internationally on children (mostly boys) whom I would consider affected with:

  • Relative shortness of stature with disproportionately larger head size and occasional craniosynostosis or parietal foramina.
  • Cowlick(s), widow’s peak, abnormal hair whorl, high forehead;
  • Relative hypertelorism, smooth upper lip, thick nasal septum, narrow ear canals;
  • Short, slightly prominent upper sternum;
  • Occasional diaphragmatic hernia,
  • Hernia(s): Belly button, groins with or without cryptorchidism;
  • Broad thumbs/big toes, curved 2nd toe nails
  • Hypospadias – usually first or 2nd degree
  • Anterior displacement or imperforate anus;
  • Urogenital anomalies ranging from unilateral agenesis, absent or duplicated uterus/vagina.
  • MRI may show absent or hypoplastic corpus callosum, delayed myelination, Blake’s pouch/”Dandy-Walker” anomaly of cerebellum, Chiari I anomaly (herniation of cerebellar tonsils), syringomyelia, tethered cord.

As important as these findings are diagnostically, I attribute equal diagnostic importance to the history of:

  • Defects of sensory integration that may involve bright lights, sounds, touch (tags in shirts), walking on grass or sand, bathing, oral hygiene, etc.
  • Mechanical fascinations: fans, wheels, dryer and washing machines, etc.
  • Relatively rigid play routines: e.g. toy cars always lined up in the same order.
  • Frustrations and meltdowns, especially in response to emotional pressure.
  • Sleep disturbances
  • Occasional obstructive sleep apnea
  • Generally a sweet, affable, loving but attention-seeking personality.
  • Schooling may present a whole new set of problems: Intolerant of a normal classroom setting, difficult peer relationships, advanced or delayed in one or more cognitive areas; behavior difficulties: “Autistic”, oppositional-defiant, obsessive-compulsive, self-absorbed, mute/speech-delayed with normal hearing, etc.


  • Commonly repeated middle ear infections, and
  • Reactive airway disease;
  • Constipation
  • Hernia repair, orchidopexy;
  • Tethered cord may require release
  • Apparent Crohn’s disease (uncommon) may require gastro-enterology evaluation.

Diagnostically I pay particular attention to the family history, especially to carrier manifestations and to potentially mildly affected relatives (mostly boys) who have “gotten by” so far.  To make the analysis easier and more accurate I strongly recommend personal evaluation of any potential carriers or potentially affected relatives.  I have the impression that this X-linked, incompletely recessive or semidominant disorder (FGS3) is rarely due to new mutations and is mostly inherited through carrier women.

But, before final conclusions are drawn, it is essential to perform an array-CGH/microarray lab analysis to be sure the potentially affected boy does not have a chromosomal microdeletion or microduplication many of which have partially overlapping FGS3 manifestations.

In my almost 50-year experience with this condition, or group of related conditions, I can only state that FGS3 is common in the population, but especially common in the special-education school age population where parents may experience untold grief with setting, teachers, counselors, administrators, and state officials administering federal and local special education service provisions.  So, please remember, that if you were to find and to enlist qualified genetic investigators wanting to tackle FGS3, that there are several hundred “case” files in my office accessible for research only with 1.) your consent and 2.) appropriate institutional investigation clearances (HIPAA, informed consent, etc.).

I am as frustrated as you at this failure to make progress in FGS3 and to “nail” this extremely important gene.  It is my hope that with an ever more competitive reduction in cost for gene-sequencing we may soon yet be successful in identifying the gene.  We know where the gene is located (Xp22.22), I   consider that a major step forward which should make the search easier  (Dessay et al., 2002).  So, do not yet give up hope – remember the 10-year search for the Huntington disease gene after it was mapped!


John M. Opitz


Dessay S, Moizard MP, Opitz JM. 2002. FG syndrome: linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3]. Amer J Med Genet 112(1):6-11.


Acknowledgment:  To my Human Genetics Colleagues Lynn Jorde and Scott Watkins for their valiant efforts to help identify the FGS3 gene in 2 local families.  And to the late Elizabeth G. Kaveggia for getting me started in FGS research.