Apert Syndrome Clinical Presentation

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 11, 2011
 

History

  • Family history is usually not significant because most cases of Apert syndrome are sporadic. A paternal age effect increases in fathers older than 50 years.
  • Headache and vomiting are signs of acute increased intracranial pressure, especially in cases of multiple suture involvement.
  • Stridor and sleep apnea indicate problems with the upper airway, resulting from craniosynostosis of sutures of the base of the skull.
  • Visual disturbance can result from corneal injury due to exposed conjunctivitis and keratitis.
  • Many patients exhibit mental retardation, although patients with normal intelligence have been reported.
Next

Physical

  • Skull and face
    • Craniostenosis is present. Coronal sutures most commonly are involved, resulting in acrocephaly, brachycephaly, turribrachycephaly, flat occiput, and high prominent forehead.
    • Large late-closing fontanels are observed.
    • A gaping midline defect is present.
    • A rare cloverleaf skull anomaly is present in approximately 4% of infants.
    • Common facial features during infancy include horizontal grooves above the supraorbital ridges that disappear with age, a break in the continuity of the eyebrows, and a trapezoid-shaped mouth at rest.
    • A flattened, often asymmetric face is observed.
    • Maxillary hypoplasia with retruded midface is present.
  • Ears, eyes, nose, and mouth
    • Patients have apparent low-set ears with occasional conductive hearing loss and congenital fixation of stapedial footplate.
    • Eyes exhibit down-slanting palpebral fissures, hypertelorism, shallow orbits, proptosis, exophthalmos, strabismus, amblyopia, optic atrophy, and, rarely, luxation of the eye globes, keratoconus, ectopic lentis, congenital glaucoma, lack of pigment in the fundi with occasional papilledema, and preventable visual loss or blindness.
    • The nose has a markedly depressed nasal bridge. It is short and wide with a bulbous tip, parrot-beaked appearance, and choanal stenosis or atresia.
    • The mouth area has a prominent mandible, down-turned corners, high arched palate, bifid uvula, and cleft palate.
    • Orthodontic problems include crowded upper teeth, malocclusion, delayed dentition, ectopic eruption, shovel-shaped incisors, supernumerary teeth, V-shaped maxillary dental arch, bulging alveolar ridges, dentitio tarda, some impaction, partial eruption, idiopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding.
  • Extremities and digits
    • The upper limbs are more severely affected than lower limbs. Coalition of distal phalanges and synonychia found in the hands is never present in the feet. The glenohumeral joint and proximal humerus are more severely affected than the pelvic girdle and femur. The elbow is much less severely involved than the proximal portion of the upper limb.
    • Syndactyly involves the hands and feet with partial-to-complete fusion of the digits, often involving second, third, and fourth digits. These are often termed mitten hands and sock feet. In severe cases, all digits are fused, with the palm deeply concave and cup-shaped and the sole supinated.
    • Hitchhiker posture or radial deviation of short or broad thumbs results from abnormal proximal phalanx.
    • Brachydactyly occurs.
    • Nailbeds are contiguous (synonychia).
    • Some patients have subacromial dimples and elbow dimples during infancy.
    • Mobility at the glenohumeral joint is limited with progressive limitation in abduction, forward flexion, and external rotation with growth.
    • Limited elbow mobility is common with decreased elbow extension, flexion, pronation, and supination.
    • Short humeri are a constant finding beyond infancy.
    • Limited genu valga is present in many cases.
  • CNS
    • Intelligence varies from normal to mental deficiency, although a significant number of patients are mentally retarded. Malformations of the CNS may be responsible for most cases.
    • Common CNS malformations include megalencephaly, agenesis of the corpus callosum, malformed limbic structures, variable ventriculomegaly, encephalocele, gyral abnormalities, hypoplastic cerebral white matter, pyramidal tract abnormalities, and heterotopic gray matter. Progressive hydrocephalus is uncommon.
    • Papilledema and optic atrophy with loss of vision may be present in cases of subtle increased intracranial pressure.
  • Other skeletal and cartilaginous segmentation defects
    • Congenital cervical spinal fusion (68%), especially C5-C6
    • Aplasia or ankylosis of shoulder, elbow, and hip joints
    • Tracheal cartilage anomalies
    • Rhizomelia
  • Skin
    • Hyperhidrosis (common)
    • Synonychia
    • Brittle nails
    • Acneiform lesions (frequent after adolescence)
    • Interruption of the eyebrows
    • Hypopigmentation
    • Hyperkeratosis in the plantar surface
    • Paronychial infections (more common in feet than hands and in patients who are institutionalized patients)
    • Excessive skin wrinkling of forehead
    • Skin dimples at knuckles, shoulders, and elbows
  • Cardiovascular (10%)
  • Genitourinary (9.6%)
    • Polycystic kidneys
    • Duplication of renal pelvis
    • Hydronephrosis
    • Stenosis of bladder neck
    • Bicornuate uterus
    • Vaginal atresia
    • Protuberant labia majora
    • Clitoromegaly
    • Cryptorchidism
  • GI (1.5%)
    • Pyloric stenosis
    • Esophageal atresia and tracheoesophageal fistula
    • Ectopic or imperforate anus
    • Partial biliary atresia with agenesis of gallbladder
  • Respiratory (1.5%)
    • Anomalous tracheal cartilage
    • Tracheoesophageal fistula
    • Pulmonary aplasia
    • Absent right middle lobe of lung
    • Absent interlobular lung fissures
Previous
Next

Causes

  • More than 98% of cases with Apert syndrome are caused by specific missense substitution mutations, involving adjacent amino acids (ie, Ser252Trp, Ser252Phe, Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of FGFR2, which maps to chromosome bands 10q26. The remaining cases are due to Alu-element insertion mutations in or near exon 9 of FGFR2.
  • Most cases are sporadic, resulting from new mutations with a paternal age effect. The incidence of FGFR2 mutations increases exponentially with paternal age, probably due to an increase in the frequency of these mutations and a selective advantage in the male germ line.[8, 9]
  • Most new mutations, estimated at 1 per 65,000 live births, imply that germline transversion rates at these 2 positions are currently the highest known in the human genome. The rarity of familial cases can be explained by reduced genetic fitness of individuals because of severe malformations and the presence of mental retardation in many cases.
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG  Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

James Bowman, MD  Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Lajeunie E, Cameron R, El Ghouzzi V, de Parseval N, Journeau P, Gonzales M. Clinical variability in patients with Apert's syndrome. J Neurosurg. Mar 1999;90(3):443-7. [Medline].

  2. Khong JJ, Anderson PJ, Hammerton M, et al. Differential effects of FGFR2 mutation in ophthalmic findings in Apert syndrome. J Craniofac Surg. Jan 2007;18(1):39-42. [Medline].

  3. Khong JJ, Anderson P, Gray TL, et al. Ophthalmic findings in apert syndrome prior to craniofacial surgery. Am J Ophthalmol. Aug 2006;142(2):328-30. [Medline].

  4. Khong JJ, Anderson PJ, Hammerton M, Roscioli T, Selva D, David DJ. Differential effects of FGFR2 mutation in ophthalmic findings in Apert syndrome. J Craniofac Surg. Jan 2007;18(1):39-42. [Medline].

  5. Cohen MM Jr, Kreiborg S, Lammer EJ, Cordero JF, Mastroiacovo P, Erickson JD. Birth prevalence study of the Apert syndrome. Am J Med Genet. Mar 1 1992;42(5):655-9. [Medline].

  6. Cohen MM Jr, Kreiborg S. An updated pediatric perspective on the Apert syndrome. Am J Dis Child. Sep 1993;147(9):989-93. [Medline].

  7. Cohen MM Jr, Kreiborg S, Lammer EJ, Cordero JF, et al. Birth prevalence study of the Apert syndrome. Am J Med Genet. Mar 1 1992;42(5):655-9. [Medline].

  8. Glaser RL, Broman KW, Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet. Oct 2003;73(4):939-47. [Medline].

  9. Goriely A, McVean GA, Rojmyr M, Ingemarsson B, Wilkie AO. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science. Aug 1 2003;301(5633):643-6. [Medline].

  10. Jabs EW, Li X, Scott AF, Meyers G, Chen W, Eccles M. Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet. Nov 1994;8(3):275-9. [Medline].

  11. Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet. Nov 1994;8(3):269-74. [Medline].

  12. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet. Sep 1994;8(1):98-103. [Medline].

  13. Rutland P, Pulleyn LJ, Reardon W, Baraitser M, Hayward R, Jones B. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nat Genet. Feb 1995;9(2):173-6. [Medline].

  14. Wilkie AO, Slaney SF, Oldridge M, Poole MD, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. Feb 1995;9(2):165-72. [Medline].

  15. Przylepa KA, Paznekas W, Zhang M, Golabi M, Bias W, Bamshad MJ, et al. Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. Nat Genet. 1996;13:492-494.

  16. Yu K, Herr AB, Waksman G, Ornitz DM. Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc Natl Acad Sci USA. 2000;97:14536-14541.

  17. Quintero-Rivera F, Robson CD, Reiss RE, et al. Apert syndrome: what prenatal radiographic findings should prompt its consideration?. Prenat Diagn. Oct 2006;26(10):966-72. [Medline].

  18. Quintero-Rivera F, Robson CD, Reiss RE, et al. Intracranial anomalies detected by imaging studies in 30 patients with Apert syndrome. Am J Med Genet A. Jun 15 2006;140(12):1337-8. [Medline].

  19. Chen H. Apert syndrome. In: Atlas of Genetic Diagnosis and Counseling. Totowa, New Jersey: Humana Press; 2006:61-69.

  20. Allanson JE. Germinal mosaicism in Apert syndrome. Clin Genet. May 1986;29(5):429-33. [Medline].

  21. Athanasiadis AP, Zafrakas M, Polychronou P, Florentin-Arar L, Papasozomenou P, Norbury G. Apert syndrome: the current role of prenatal ultrasound and genetic analysis in diagnosis and counselling. Fetal Diagn Ther. 2008;24(4):495-8. [Medline].

  22. David AL, Turnbull C, Scott R, et al. Diagnosis of Apert syndrome in the second-trimester using 2D and 3D ultrasound. Prenat Diagn. Jul 2007;27(7):629-32. [Medline].

  23. Oldridge M, Zackai EH, McDonald-McGinn DM, Iseki S, et al. De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am J Hum Genet. Feb 1999;64(2):446-61. [Medline].

  24. Raymond FL, Whittaker J, Jenkins L, Lench N, Chitty LS. Molecular prenatal diagnosis: the impact of modern technologies. Prenat Diagn. Jul 2010;30(7):674-81. [Medline].

  25. Au PK, Kwok YK, Leung KY, Tang LY, Tang MH, Lau ET. Detection of the S252W mutation in fibroblast growth factor receptor 2 (FGFR2) in fetal DNA from maternal plasma in a pregnancy affected by Apert syndrome. Prenat Diagn. Feb 2011;31(2):218-20. [Medline].

  26. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

  27. Apert M. De l'acrocephalosyndactylie. Bull Mém Soc Med Hop Paris. 1906;23:1310-1313.

  28. Blank CE. Apert's syndrome (a type of acrocephalosyndactyly). Observations on a British series of thirty-nine cases. Ann Hum Genet. 1960;24:151-64.

  29. Chang CC, Tsai FJ, Tsai HD, et al. Prenatal diagnosis of Apert syndrome. Prenat Diagn. 1998;18:621-5.

  30. Cohen MM Jr. Craniosynostoses: phenotypic/molecular correlations. Am J Med Genet. Apr 10 1995;56(3):334-9. [Medline].

  31. Cohen MM Jr. Craniosynostosis update 1987. Am J Med Genet Suppl. 1988;4:99-148. [Medline].

  32. Cohen MM Jr, ed. Craniosynostosis: Diagnosis, evaluation, and management. New York, NY: Raven Press; 1986.

  33. Cohen MM Jr, Kreiborg S. Cutaneous manifestations of Apert syndrome. Am J Med Genet. Jul 31 1995;58(1):94-6. [Medline].

  34. Cohen MM Jr, Kreiborg S. Hands and feet in the Apert syndrome. Am J Med Genet. May 22 1995;57(1):82-96. [Medline].

  35. Cohen MM Jr, Kreiborg S. Skeletal abnormalities in the Apert syndrome. Am J Med Genet. Oct 1 1993;47(5):624-32. [Medline].

  36. Cohen MM Jr, Kreiborg S. The central nervous system in the Apert syndrome. Am J Med Genet. Jan 1990;35(1):36-45. [Medline].

  37. Cohen MM Jr, Kreiborg S. Visceral anomalies in the Apert syndrome. Am J Med Genet. Mar 15 1993;45(6):758-60. [Medline].

  38. Cuerda E, del Pozo J, Rodriguez-Lozano J, Pena-Penabad C, Fonseca E. Acne in Apert's syndrome: treatment with isotretinoin. J Dermatolog Treat. Jan 2003;14(1):43-5. [Medline].

  39. Cunningham ML, Seto ML, Ratisoontorn C, Heike CL, Hing AV. Syndromic craniosynostosis: from history to hydrogen bonds. Orthod Craniofac Res. May 2007;10(2):67-81. [Medline].

  40. DeGiovanni CV, Jong C, Woollons A. What syndrome is this? Apert syndrome. Pediatr Dermatol. Mar-Apr 2007;24(2):186-8. [Medline].

  41. Do Amaral CMR, Di Domizio G, Buzzo CL. Surgical treatment of Apert syndrome and Crouzon anomaly by gradual bone distraction. Plast Reconstr Surg. Sept 2009;124(3).

  42. Erickson JD, Cohen MM Jr. A study of parental age effects on the occurrence of fresh mutations for the Apert syndrome. Ann Hum Genet. Jul 1974;38(1):89-96. [Medline].

  43. Freiman A, Tessler O, Barankin B. Apert syndrome. Int J Dermatol. Nov 2006;45(11):1341-3. [Medline].

  44. Hansen WF, Rijhsinghani A, Grant S, Yankowitz J. Prenatal diagnosis of Apert syndrome. Fetal Diagn Ther. Mar-Apr 2004;19(2):127-30. [Medline].

  45. Hohoff A, Joos U, Meyer U, Ehmer U, Stamm T. The spectrum of Apert syndrome: phenotype, particularities in orthodontic treatment, and characteristics of orthognathic surgery. Head Face Med. 2007;3:10. [Medline]. [Full Text].

  46. Kan SH, Elanko N, Johnson D, et al. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am J Hum Genet. Feb 2002;70(2):472-86. [Medline]. [Full Text].

  47. Kaplan L. Clinical assessment and multispeciality management of Apert syndrome. Clin Plast Surg. 1991;18:217-225.

  48. Kreiborg S, Cohen MM Jr. Characteristics of the infant Apert skull and its subsequent development. J Craniofac Genet Dev Biol. 1990;10(4):399-410. [Medline].

  49. Leonard CO, Daikotu NH, Winn K. Prenatal fetoscopic diagnosis of the Apert syndrome. Am J Med Genet. 1982;11:5-9.

  50. Liptak GS, Serletti JM. Pediatric approach to craniosynostosis. Pediatr Rev. Oct 1998;19(10):352; quiz 359. [Medline].

  51. Lomri A, Lemonnier J, Hott M, de Parseval N, et al. Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome. J Clin Invest. Mar 15 1998;101(6):1310-7. [Medline].

  52. Mahieu-Caputo D, Sonigo P, Amiel J, Simon I, Aubry MC, Lemerrer M. Prenatal diagnosis of sporadic Apert syndrome: a sequential diagnostic approach combining three-dimensional computed tomography and molecular biology. Fetal Diagn Ther. Jan-Feb 2001;16(1):10-2. [Medline].

  53. Moloney DM, Slaney SF, Oldridge M, Wall SA, et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet. May 1996;13(1):48-53. [Medline].

  54. Narayan H, Scott IV. Prenatal ultrasound diagnosisof Apert's syndrome. Prenat Diagn. 1991;10:187-192.

  55. Park WJ, Theda C, Maestri NE, Meyers GA, et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet. Aug 1995;57(2):321-8. [Medline].

  56. Rajenderkumar D, Bamiou D, Sirimanna T. Management of hearing loss in Apert syndrome. J Laryngol Otol. May 2005;119(5):385-90. [Medline].

  57. Renier D, Arnaud E, Cinalli G, Sebag G, Zerah M, Marchac D. Prognosis for mental function in Apert's syndrome. J Neurosurg. Jul 1996;85(1):66-72. [Medline].

  58. Slaney SF, Oldridge M, Hurst JA, et al. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet. May 1996;58(5):923-32. [Medline].

  59. Tay T, Martin F, Rowe N, et al. Prevalence and causes of visual impairment in craniosynostotic syndromes. Clin Experiment Ophthalmol. Jul 2006;34(5):434-40. [Medline].

  60. Thompson DN, Slaney SF, Hall CM, Shaw D, et al. Congenital cervical spinal fusion: a study in Apert syndrome. Pediatr Neurosurg. Jul 1996;25(1):20-7. [Medline].

  61. Tolarova MM, Harris JA, Ordway DE, Vargervik K. Birth prevalence, mutationrate, sex ratio, parents' age, and ethnicity in Apert syndrome. Am J Med Genet. 1997;72:394-398.

  62. Verma S, Draznin M. Apert syndrome. Dermatol Online J. 2005;11:15-18. [Medline].

  63. von Gernet S, Golla A, Ehrenfels Y, Schuffenhauer S, Fairley JD. Genotype-phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery. Clin Genet. 2000;57:137-139.

 
Previous
Next
 
An infant with Apert syndrome is shown. Note the characteristic ocular hypertelorism, down-slanting palpebral fissures, proptotic eyes, horizontal groove above the supraorbital ridge, break of the continuity of eyebrows, depressed nasal bridge, and short wide nose with bulbous tip.
Note the mitten appearance of the hands with syndactyly involving the second, third, fourth, and fifth fingers. This patient also has characteristic concave palms, hitchhiker posture (radial deviation) of short broad thumbs, and contiguous nailbeds (synonychia).
Note the sock appearance of the feet with syndactyly involving the second, third, fourth, and fifth toes. The patient also has contiguous nail beds (synonychia).
In this profile, turribrachycephaly, high prominent forehead, proptosis, depressed nasal bridge, short nose, and low-set ears are prominent.
This radiograph demonstrates turribrachycephaly, shallow orbits, ocular hypertelorism, and hypoplastic maxilla.
Note osseous syndactyly involving the second, third, fourth, and fifth fingers; multiple synostosis involving distal phalanges and proximal fourth and fifth metacarpals; symphalangism of interphalangeal joints; shortening and radial deviation of distal phalanx; and delta-shaped deformity of proximal phalanx of the thumbs.
Note osseous syndactyly, fusion of interphalangeal joints, synostosis involving proximal first and second metatarsals, and partially duplicated and delta-shaped proximal phalanx of the great toes.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.