Pfeiffer syndrome

Pfeiffer syndrome
Pfeiffer syndrome type 2 with cloverleaf-shaped skull and bilateral proptosis before and after surgery
CausesGenetic[1]
Frequency1 per 100,000 births[1]

Pfeiffer syndrome is a rare genetic disorder characterized by the premature fusion of certain bones of the skull (craniosynostosis) which affects the shape of the head and face. In addition, the syndrome includes abnormalities of the hands (such as wide and deviated thumbs) and feet (such as wide and deviated big toes).

Pfeiffer syndrome is caused by mutations in the fibroblast growth factor receptors FGFR1 and FGFR2. The syndrome is grouped into three types, type 1 (classic Pfeiffer syndrome) being milder and caused by mutations in either gene and types 2 and 3 being more severe, often leading to death in infancy, caused by mutations in FGFR2.[2]

There is no cure for the syndrome. Treatment is supportive and often involves surgery in the earliest years of life to correct skull deformities and respiratory function.[2] Most individuals with Pfeiffer syndrome type 1 have a normal intelligence and life span, while types 2 and 3 typically result in neurodevelopmental disorders and early death.

Pfeiffer syndrome affects about 1 in 100,000 births.[1] The syndrome is named after German geneticist Rudolf Arthur Pfeiffer (1931–2012), who described it in 1964.[3]

Signs and symptoms

Ocular proptosis, turricephaly, maxillary hypoplasia

Many of the characteristic facial features result from the premature fusion of the skull bones (craniosynostosis). The head is unable to grow normally, which leads to a high prominent forehead (turribrachycephaly), and eyes that appear to bulge (proptosis) and are wide-set (hypertelorism). In addition, there is an underdeveloped upper jaw (maxillary hypoplasia). More than 50 percent of children with Pfeiffer syndrome have hearing loss; dental problems are also common.[4]

In people with Pfeiffer syndrome, the thumbs and first (big) toes are wide and bend away from the other digits (pollex varus and hallux varus). Unusually short fingers and toes (brachydactyly) are also common, and there may be some webbing or fusion between the digits (syndactyly).[5]

Cause

Pfeiffer syndrome is strongly associated with mutations of the fibroblast growth factor receptor 1 (FGFR1) on chromosome 8 or the fibroblast growth factor receptor 2 (FGFR2) gene on chromosome 10.[1][6][7][8] These genes code for fibroblast growth factor receptors, which are important for normal bone development.[9] Advanced paternal age is thought to be a risk factor for sporadic cases of Pfeiffer syndrome due to an increase in mutations in sperm as men become older.[1][10]

Diagnosis

Classification

The most widely accepted clinical classification of Pfeiffer syndrome was published by M. Michael Cohen in 1993.[1][11] Cohen divided the syndrome into three possibly overlapping types, all of which are characterized by broad thumbs, broad great toes, brachydactyly and possibly syndactyly:[12]

  • Type 1, also known as classic Pfeiffer syndrome, includes craniosynostosis and "midface deficiency". This type is inherited in an autosomal dominant pattern. Most individuals with type 1 Pfeiffer syndrome have normal intelligence and a normal life span.
  • Type 2 includes a cloverleaf-shaped skull, due to extensive fusion of bones, as well as severe proptosis. This type occurs sporadically (i.e., does not appear to be inherited) and has "a poor prognosis and severe neurological compromise, generally with early death".
  • Type 3 includes craniosynostosis and severe proptosis. This type occurs sporadically (i.e., does not appear to be inherited) and has "a poor prognosis and severe neurological compromise, generally with early death."

Management

The key problem is the early fusion of the skull, which can be corrected by a series of surgical procedures, often within the first three months after birth. Later surgeries are necessary to correct respiratory and facial deformities.[2]

Outcomes

Children with Pfeiffer syndrome types 2 and 3 "have a higher risk for neurodevelopmental disorders and a reduced life expectancy" than children with Pfeiffer syndrome type 1, but if treated, favorable outcomes are possible.[13] In severe cases, respiratory and neurological complications often lead to early death.

History

The syndrome is named after German geneticist Rudolf Arthur Pfeiffer (1931–2012).[14] In 1964, Pfeiffer described eight individuals in three generations of a family who had abnormalities of the head, hands and feet (acrocephalosyndactylia) that were inherited in an autosomal dominant pattern.[1][12][3]

Notable cases

  • In 1996, a son was born to American musician Prince and his wife Mayte Garcia. The highly anticipated child, Amiir ("prince" in Arabic), was diagnosed at birth with Pfeiffer syndrome type 2 and died several days later.[15] In 1997, after Garcia's former personal assistants raised concerns about the manner of death, the medical examiner performed an investigation and declared that the death was due to natural causes (meaning it was not a homicide).[16]
  • In 2014, the mother of a boy in Texas with Pfeiffer syndrome type 1 posted a photograph of the child to her blog. In 2016, she discovered that the photograph had been used in a meme comparing her son to a pug. Her efforts to remove the meme from the Internet, especially social media such as Instagram, Twitter, and Facebook, attracted international attention.[17][18][19]

References

  1. 1 2 3 4 5 6 7 Vogels A, Fryns JP (2006). "Pfeiffer syndrome". Orphanet J Rare Dis. 1: 19. doi:10.1186/1750-1172-1-19. PMC 1482682. PMID 16740155.
  2. 1 2 3 "Pfeiffer Syndrome". NORD (National Organization for Rare Disorders). Archived from the original on 2019-04-14. Retrieved 2019-09-03.
  3. 1 2 Pfeiffer RA (1964). "Dominant erbliche Akrocephalosyndaktylie" [Dominant Hereditary Acrocephalosyndactylia]. Zeitschrift für Kinderheilkunde (in Deutsch). 90 (4): 301–20. doi:10.1007/BF00447500. PMID 14316612. S2CID 35706808.
  4. ↑ "Pfeiffer syndrome". U.S. National Library of Medicine. Archived from the original on 2020-10-19. Retrieved 2020-10-29.
  5. ↑ "Pfeiffer syndrome". U.S. National Library of Medicine. Archived from the original on 2020-10-19. Retrieved 2020-10-29.
  6. ↑ Muenke M; Schell U; Hehr A; Robin NH; Losken HW; Schinzel A; et al. (1994). "A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome". Nat Genet. 8 (3): 269–74. doi:10.1038/ng1194-269. PMID 7874169. S2CID 40033932.
  7. ↑ Rutland P; Pulleyn LJ; Reardon W; Baraitser M; Hayward R; Jones B; et al. (1995). "Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes". Nat Genet. 9 (2): 173–6. doi:10.1038/ng0295-173. PMID 7719345. S2CID 927144.
  8. ↑ Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, et al. (1995). "Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome". Hum Mol Genet. 4 (3): 323–8. doi:10.1093/hmg/4.3.323. PMID 7795583.
  9. ↑ Chan CT, Thorogood P (1999). "Pleiotropic features of syndromic craniosynostoses correlate with differential expression of fibroblast growth factor receptors 1 and 2 during human craniofacial development". Pediatr. Res. 45 (1): 46–53. doi:10.1203/00006450-199901000-00008. PMID 9890607.
  10. ↑ Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, et al. (2000). "Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome". Am J Hum Genet. 66 (3): 768–77. doi:10.1086/302831. PMC 1288162. PMID 10712195.
  11. ↑ National Institutes of Health, Genetic and Rare Diseases (GARD) Information Center (2016-04-01). "Pfeiffer syndrome: Symptoms". Archived from the original on 2016-05-09. Retrieved 2016-05-08.
  12. 1 2 Cohen MM (1993). "Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis". Am J Med Genet. 45 (3): 300–7. doi:10.1002/ajmg.1320450305. PMID 8434615.
  13. ↑ Robin NH; Scott JA; Arnold JE; Goldstein JA; Shilling BB; Marion RW; et al. (1998). "Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification". Am J Med Genet. 75 (3): 240–4. doi:10.1002/(sici)1096-8628(19980123)75:3<240::aid-ajmg2>3.3.co;2-c. PMID 9475589.
  14. ↑ synd/3477 at Who Named It?
  15. ↑ Lerner, Maura (1997-03-28). "Prince's court case touches on 2 issues: A family's right to privacy, medical ethics". Star Tribune. Minneapolis – via NewsBank.
  16. ↑ Chanen, David (1997-06-14). "Ruling: Prince's baby died from natural causes". Star Tribune. Minneapolis – via NewsBank.
  17. ↑ Pelletiere, Nicole (2016-02-02). "Mom Defends Son Against Offensive Internet Meme". ABC News. Archived from the original on 2016-05-19. Retrieved 2016-05-08.
  18. ↑ Hernandez, Vittorio (2016-02-05). "Texas mum mad at use of photo of son with rare disorder Pfeiffer syndrome to make cruel memes". International Business Times, Australia Edition. Archived from the original on 2016-04-04. Retrieved 2016-05-08.
  19. ↑ "Mutter wehrt sich gegen Witze, die auf Kosten ihres kranken Sohnes gemacht werden" [Mother defends against jokes that are made at the expense of her sick son]. Stern (in Deutsch). 2016-02-08. Archived from the original on 2016-05-07. Retrieved 2016-05-08.
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