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Pfeiffer syndrome(ACS5)

MedGen UID:
67390
Concept ID:
C0220658
Disease or Syndrome
Synonyms: Acrocephalosyndactyly, type 5; ACS V; ACS5; FGFR1-Related Craniosynostosis; Pfeiffer type acrocephalosyndactyly
SNOMED CT: Pfeiffer syndrome (70410008); Pfeiffer-type acrocephalosyndactyly (70410008); Acrocephalosyndactyly type V (70410008); Acrocephalosyndactyly type 5 (70410008)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Genes (locations): FGFR1 (8p11.23); FGFR2 (10q26.13)
 
Monarch Initiative: MONDO:0007043
OMIM®: 101600
Orphanet: ORPHA710

Definition

Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (Cohen, 1993). Cohen and Barone (1994) further tabulated the findings in the 3 types of Pfeiffer syndrome. [from OMIM]

Additional description

From MedlinePlus Genetics
Pfeiffer syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Pfeiffer syndrome also affects bones in the hands and feet.

Many of the characteristic facial features of Pfeiffer syndrome result from premature fusion of the skull bones. Abnormal growth of these bones leads to bulging and wide-set eyes, a high forehead, an underdeveloped upper jaw, and a beaked nose. More than half of all children with Pfeiffer syndrome have hearing loss; dental problems are also common.

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

Pfeiffer syndrome is divided into three subtypes. Type 1, also known as classic Pfeiffer syndrome, has symptoms as described above. Most individuals with type 1 Pfeiffer syndrome have normal intelligence and a normal life span. Types 2 and 3 are more severe forms of Pfeiffer syndrome that often involve problems with the nervous system. The premature fusion of skull bones can limit brain growth, leading to delayed development and other neurological problems. In addition, individuals with type 2 or 3 can have fusion of the bones (ankylosis) in the elbow or other joints, limiting mobility, and abnormalities of the face and airways, which can cause life-threatening breathing problems. Type 2 is distinguished from type 3 by the presence of a cloverleaf-shaped head, which is caused by more extensive fusion of bones in the skull.  https://medlineplus.gov/genetics/condition/pfeiffer-syndrome

Clinical features

From HPO
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Finger syndactyly
MedGen UID:
65139
Concept ID:
C0221352
Congenital Abnormality
Webbing or fusion of the fingers, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" Syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers in a proximo-distal axis are referred to as "Symphalangism".
Broad thumb
MedGen UID:
140880
Concept ID:
C0426891
Finding
Increased thumb width without increased dorso-ventral dimension.
Shortening of all middle phalanges of the fingers
MedGen UID:
347331
Concept ID:
C1856912
Finding
Short, hypoplastic middle phalanx of finger, affecting all fingers.
Broad hallux
MedGen UID:
401165
Concept ID:
C1867131
Finding
Visible increase in width of the hallux without an increase in the dorso-ventral dimension.
Humeroradial synostosis
MedGen UID:
418931
Concept ID:
C2930865
Disease or Syndrome
An abnormal osseous union (fusion) between the radius and the humerus.
Short middle phalanx of toe
MedGen UID:
867359
Concept ID:
C4021723
Anatomical Abnormality
Developmental hypoplasia (shortening) of middle phalanx of toe.
3-4 toe cutaneous syndactyly
MedGen UID:
1052578
Concept ID:
CN377480
Finding
A soft tissue continuity in the anteroposterior axis between the toes 3 and 4.
Chiari malformation
MedGen UID:
2065
Concept ID:
C0003803
Congenital Abnormality
Chiari malformation consists of a downward displacement of the cerebellar tonsils and the medulla through the foramen magnum, sometimes causing hydrocephalus as a result of obstruction of CSF outflow.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypoplasia of the maxilla
MedGen UID:
66804
Concept ID:
C0240310
Congenital Abnormality
Abnormally small dimension of the Maxilla. Usually creating a malocclusion or malalignment between the upper and lower teeth or resulting in a deficient amount of projection of the base of the nose and lower midface region.
Elbow ankylosis
MedGen UID:
592439
Concept ID:
C0409477
Disease or Syndrome
Coronal craniosynostosis
MedGen UID:
344694
Concept ID:
C1856266
Congenital Abnormality
Premature closure of the coronal suture of skull.
Brachyturricephaly
MedGen UID:
387833
Concept ID:
C1857484
Finding
Abnormal vertical height of the skull and a shortening of its anterior-posterior length, frequently combined with malformations of the occipital region.
Cloverleaf skull
MedGen UID:
348010
Concept ID:
C1860050
Congenital Abnormality
Trilobar skull configuration when viewed from the front or behind.
Shallow orbits
MedGen UID:
351328
Concept ID:
C1865244
Finding
Reduced depth of the orbits associated with prominent-appearing ocular globes.
Bronchomalacia
MedGen UID:
82679
Concept ID:
C0264353
Disease or Syndrome
Weakness or softness of the cartilage in the walls of the bronchial tubes.
Tracheal cartilaginous sleeve
MedGen UID:
1813071
Concept ID:
C5676597
Congenital Abnormality
Tracheal cartilaginous sleeve (TCS) is a rare congenital airway malformation in which distinct tracheal rings are replaced by a continuous cartilaginous segment. Vertically fused C- or O-shaped cartilaginous rings can extend from the subglottis to the carina or bronchus with little to no pars membranacea posteriorly. Comment:Tracheal cartilaginous sleeve has been associated with various craniosynostosis syndromes.
Choanal atresia
MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Choanal stenosis
MedGen UID:
108427
Concept ID:
C0584837
Finding
Abnormal narrowing of the choana (the posterior nasal aperture).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Professional guidelines

PubMed

Kutkowska-Kaźmierczak A, Gos M, Obersztyn E
J Appl Genet 2018 May;59(2):133-147. Epub 2018 Feb 1 doi: 10.1007/s13353-017-0423-4. PMID: 29392564
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Fearon JA, Rhodes J
Plast Reconstr Surg 2009 May;123(5):1560-1569. doi: 10.1097/PRS.0b013e3181a2057e. PMID: 19407629

Recent clinical studies

Etiology

Lu X, Forte AJ, Allam O, Park KE, Wilson A, Alperovich M, Steinbacher DM, Tonello C, Alonso N, Persing JA
Plast Reconstr Surg 2022 Apr 1;149(4):731e-742e. doi: 10.1097/PRS.0000000000008928. PMID: 35171849
Raposo-Amaral CE, de Oliveira YM, Denadai R, Raposo-Amaral CA, Ghizoni E
Childs Nerv Syst 2021 Jun;37(6):2001-2009. Epub 2021 Apr 18 doi: 10.1007/s00381-021-05169-w. PMID: 33866411
Bautista G
Neoreviews 2021 Apr;22(4):e250-e257. doi: 10.1542/neo.22-4-e250. PMID: 33795400
Rogers GF, Greene AK, Proctor MR, Mulliken JB, Goobie SM, Stoler JM
Cleft Palate Craniofac J 2015 Nov;52(6):751-7. Epub 2014 Oct 28 doi: 10.1597/14-092. PMID: 25350344
Harb E, Kran B
Optometry 2005 Jul;76(7):352-62. doi: 10.1016/j.optm.2005.05.002. PMID: 16038862

Diagnosis

Mavridis IN, Rodrigues D
Childs Nerv Syst 2021 Feb;37(2):367-374. Epub 2020 Oct 20 doi: 10.1007/s00381-020-04934-7. PMID: 33083874
Lesciotto KM, Heuzé Y, Jabs EW, Bernstein JM, Richtsmeier JT
Plast Reconstr Surg 2018 Jan;141(1):156-168. doi: 10.1097/PRS.0000000000003928. PMID: 29280877Free PMC Article
Wang JC, Nagy L, Demke JC
Facial Plast Surg Clin North Am 2016 Nov;24(4):531-543. doi: 10.1016/j.fsc.2016.06.008. PMID: 27712819
Rogers GF, Greene AK, Proctor MR, Mulliken JB, Goobie SM, Stoler JM
Cleft Palate Craniofac J 2015 Nov;52(6):751-7. Epub 2014 Oct 28 doi: 10.1597/14-092. PMID: 25350344
Vogels A, Fryns JP
Orphanet J Rare Dis 2006 Jun 1;1:19. doi: 10.1186/1750-1172-1-19. PMID: 16740155Free PMC Article

Therapy

Venkat Raman V, de Beer D
Paediatr Anaesth 2021 Dec;31(12):1316-1324. Epub 2021 Oct 21 doi: 10.1111/pan.14310. PMID: 34623012
Raposo-Amaral CE, de Oliveira YM, Denadai R, Raposo-Amaral CA, Ghizoni E
Childs Nerv Syst 2021 Jun;37(6):2001-2009. Epub 2021 Apr 18 doi: 10.1007/s00381-021-05169-w. PMID: 33866411
Frassanito P, Palombi D, Tamburrini G
Childs Nerv Syst 2021 Nov;37(11):3465-3473. Epub 2021 Apr 7 doi: 10.1007/s00381-021-05158-z. PMID: 33829280
Morice A, Paternoster G, Ostertag A, James S, Cohen-Solal M, Khonsari RH, Arnaud E
Plast Reconstr Surg 2018 Feb;141(2):437-445. doi: 10.1097/PRS.0000000000004040. PMID: 29036029
Su PH, Chen JY, Lee IC, Ng YY, Hu JM, Chen SJ
Pediatr Neonatol 2009 Oct;50(5):234-8. doi: 10.1016/S1875-9572(09)60069-3. PMID: 19856868

Prognosis

Vimercati A, Olivieri C, Dellino M, Gentile M, Tinelli R, Cicinelli E
J Matern Fetal Neonatal Med 2022 Dec;35(25):7840-7843. Epub 2021 Jun 28 doi: 10.1080/14767058.2021.1937984. PMID: 34182859
Lu X, Forte AJ, Allam O, Park KE, Junn A, Alperovich M, Steinbacher DM, Tonello C, Alonso N, Persing JA
Br J Oral Maxillofac Surg 2021 Jun;59(5):592-598. Epub 2020 Dec 15 doi: 10.1016/j.bjoms.2020.10.008. PMID: 33863588
Mavridis IN, Rodrigues D
Childs Nerv Syst 2021 Feb;37(2):367-374. Epub 2020 Oct 20 doi: 10.1007/s00381-020-04934-7. PMID: 33083874
Harada A, Miyashita S, Nagai R, Makino S, Murotsuki J
Congenit Anom (Kyoto) 2019 Jul;59(4):132-141. Epub 2018 Sep 5 doi: 10.1111/cga.12308. PMID: 30132994
Nur BG, Pehlivanoğlu S, Mıhçı E, Calışkan M, Demir D, Alper OM, Kayserili H, Lüleci G
Pediatr Neurol 2014 May;50(5):482-90. Epub 2014 Jan 11 doi: 10.1016/j.pediatrneurol.2014.01.023. PMID: 24656465

Clinical prediction guides

Lu X, Forte AJ, Allam O, Park KE, Wilson A, Alperovich M, Steinbacher DM, Tonello C, Alonso N, Persing JA
Plast Reconstr Surg 2022 Apr 1;149(4):731e-742e. doi: 10.1097/PRS.0000000000008928. PMID: 35171849
Raposo-Amaral CE, de Oliveira YM, Denadai R, Raposo-Amaral CA, Ghizoni E
Childs Nerv Syst 2021 Jun;37(6):2001-2009. Epub 2021 Apr 18 doi: 10.1007/s00381-021-05169-w. PMID: 33866411
Mavridis IN, Rodrigues D
Childs Nerv Syst 2021 Feb;37(2):367-374. Epub 2020 Oct 20 doi: 10.1007/s00381-020-04934-7. PMID: 33083874
Collmann H, Sörensen N, Krauss J
Childs Nerv Syst 2005 Oct;21(10):902-12. Epub 2005 Apr 27 doi: 10.1007/s00381-004-1116-y. PMID: 15864600
Müller U, Steinberger D, Kunze S
Graefes Arch Clin Exp Ophthalmol 1997 Sep;235(9):545-50. doi: 10.1007/BF00947081. PMID: 9342602

Recent systematic reviews

Tcherbbis Testa V, Jaimovich S, Argañaraz R, Mantese B
Acta Neurochir (Wien) 2021 Nov;163(11):3083-3091. Epub 2021 Sep 27 doi: 10.1007/s00701-021-04980-3. PMID: 34570275
Mavridis IN, Rodrigues D
Childs Nerv Syst 2021 Feb;37(2):367-374. Epub 2020 Oct 20 doi: 10.1007/s00381-020-04934-7. PMID: 33083874

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