Genetics

The Genetic Blueprint: Understanding FGFR2 Mutations

At a Glance

Apert syndrome is almost always caused by a spontaneous mutation in the FGFR2 gene, specifically the S252W or P253R variations. This mutation acts as a biological switch stuck in the 'on' position, causing premature fusion of skull bones and webbing of the fingers and toes.

Understanding the genetics of Apert syndrome can help you make sense of your child’s diagnosis and prepare for their future care. This condition is caused by a very specific change in a single gene that acts as a master switch for bone development.

The Biological “Master Switch”

Apert syndrome is caused by a mutation in the FGFR2 gene ^[1]. This gene provides instructions for making a protein called fibroblast growth factor receptor 2. Think of this protein as a “receiver” on the surface of cells that waits for chemical signals telling the cell to grow, divide, or turn into bone ^[2].

In Apert syndrome, the mutation is a gain-of-function mutation ^[3]. This means the “receiver” is stuck in the “on” position, constantly sending signals to the cell even when it shouldn’t ^[2]. This overactive signaling causes:

Early Bone Fusion: In the skull, cells turn into bone too quickly, causing the growth plates (sutures) to fuse before the brain has finished growing ^[4].
Limb Differences: In the hands and feet, the signals that normally tell the body to separate fingers and toes are disrupted, leading to the characteristic “mitten” fusion (syndactyly) ^[5].

The Two Main Mutations

Nearly all cases of Apert syndrome (about 98%) are caused by one of two specific changes in the FGFR2 gene. You can find out which specific mutation your child has by looking at their official genetic testing report, which your geneticist or pediatrician will provide. While they cause the same syndrome, they can lead to slightly different clinical patterns:

Feature	S252W (p.Ser252Trp)	P253R (p.Pro253Arg)
Cleft Palate	Significantly more common ^[6]^[7]	Less frequent ^[6]
Sleep Apnea	Often more severe due to airway shape ^[8]	Generally less severe ^[8]
Hand Severity	Symmetrical “mitten” fusion ^[9]	Often more severe syndactyly ^[8]
Speech/Hearing	Higher risk for severe challenges ^[6]	Often less severe challenges ^[6]

While some studies suggest S252W may be associated with more significant cognitive challenges, intelligence varies widely in both groups and is heavily influenced by early surgery and the child’s environment ^[10]^[11].

How Did This Happen?

It is natural for parents to wonder if they did something to cause this. It is important to know that Apert syndrome is almost always a de novo mutation ^[12]. This means the change happened spontaneously in either the egg or the sperm at the time of conception; it was not present in the parents’ DNA and could not have been prevented ^[5].

Apert syndrome follows an autosomal dominant pattern of inheritance ^[1]. This means:

One Copy is Enough: A person only needs one mutated copy of the FGFR2 gene to have the syndrome ^[13].
Future Risks: Because most cases are “de novo,” the risk of a second child having Apert syndrome is extremely low (less than 1%) ^[12]. However, an individual with Apert syndrome has a 50% chance of passing the gene on to their own children ^[14].

Note: In some cases, advanced paternal age (fathers over 35) has been associated with a slightly higher chance of these spontaneous mutations occurring ^[15].

Common questions in this guide

Did I do something to cause my child's Apert syndrome?

No. Apert syndrome is almost always the result of a spontaneous 'de novo' mutation that occurs at the time of conception. It was not present in your DNA beforehand, meaning you did nothing to cause it and it could not have been prevented.

What is the difference between the S252W and P253R mutations?

While both mutations cause Apert syndrome, they can lead to different features. The S252W mutation carries a higher risk for cleft palate and severe sleep apnea. The P253R mutation is typically associated with more severe 'mitten' fusions in the hands and feet.

What are the chances of having another child with Apert syndrome?

Because most cases happen spontaneously at conception, the risk of parents having a second child with Apert syndrome is very low (less than 1%). However, when your child grows up, they will have a 50% chance of passing the condition to their own children.

How does the FGFR2 mutation affect my child's bone development?

The mutated FGFR2 gene produces a protein that acts like a receiver stuck in the 'on' position. It constantly sends signals telling cells to turn into bone, which causes the skull plates to fuse before the brain finishes growing and prevents the fingers and toes from separating.

Curated prompts to bring to your next appointment.

1.Which specific mutation did the genetic testing reveal for my child (S252W or P253R)?
2.Based on this specific mutation, what is my child's individual risk for developing a cleft palate or severe sleep apnea?
3.How does my child's mutation affect the surgical plan for their hands and feet?
4.Since this was a 'de novo' mutation, what does that mean for our family's future planning and the risk for our other children?
5.Can you explain how this mutation specifically changed the way my child's skull and limb cells developed before birth?

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References (15)

1
Apert syndrome: craniofacial challenges and clinical implications.
Singh N, Verma P, Bains R, Mutalikdesai J
BMJ case reports 2024; (17(7)) doi:10.1136/bcr-2024-260724.
PMID: 39013624
2
The Effect of Yes-Associated Protein on the Interaction Between the MEK/Extracellular Signal-Regulated Kinase and Hippo Pathways in Osteoblasts Co-Cultured With Fibroblast Growth Factor Receptor 2-Mutated Dura Cells.
Dong X, Zhang M, Li C, et al.
The Journal of craniofacial surgery 2022; (33(4)):1250-1254 doi:10.1097/SCS.0000000000008115.
PMID: 36041089
3
Mandibular dysmorphology due to abnormal embryonic osteogenesis in FGFR2-related craniosynostosis mice.
Motch Perrine SM, Wu M, Stephens NB, et al.
Disease models & mechanisms 2019; (12(5)) doi:10.1242/dmm.038513.
PMID: 31064775
4
Genetic Polymorphisms in FGFR2 Underlie Skeletal Malocclusion.
Jiang Q, Mei L, Zou Y, et al.
Journal of dental research 2019; (98(12)):1340-1347 doi:10.1177/0022034519872951.
PMID: 31509720
5
Tripod-shaped Syndactyly in Apert Syndrome with FGFR2 p.P253R Mutation.
Singh CB, Mishra B, Patel R, et al.
Indian journal of plastic surgery : official publication of the Association of Plastic Surgeons of India 2021; (54(3)):370-372 doi:10.1055/s-0041-1733808.
PMID: 34667527
6
Hearing, Speech, Language, and Communicative Participation in Patients With Apert Syndrome: Analysis of Correlation With Fibroblast Growth Factor Receptor 2 Mutation.
Kilcoyne S, Luscombe C, Scully P, et al.
The Journal of craniofacial surgery 2022; (33(1)):243-250 doi:10.1097/SCS.0000000000008019.
PMID: 34310431
7
Cleft Palate in Apert Syndrome.
Willie D, Holmes G, Jabs EW, Wu M
Journal of developmental biology 2022; (10(3)) doi:10.3390/jdb10030033.
PMID: 35997397
8
Genetic Subtypes of Apert Syndrome Are Associated With Differences in Airway Morphology and Early Upper Airway Obstruction.
Wagner CS, Wietlisbach LE, Kota A, et al.
The Journal of craniofacial surgery 2023; (34(7)):1999-2003 doi:10.1097/SCS.0000000000009583.
PMID: 37582295
9
Mutations in the FGFR2 gene in Mexican patients with Apert syndrome.
Ibarra-Arce A, Ortiz de Zárate-Alarcón G, Flores-Peña LG, et al.
Genetics and molecular research : GMR 2015; (14(1)):2341-6 doi:10.4238/2015.March.27.19.
PMID: 25867380
10
Apert and Crouzon syndromes-Cognitive development, brain abnormalities, and molecular aspects.
Fernandes MB, Maximino LP, Perosa GB, et al.
American journal of medical genetics. Part A 2016; (170(6)):1532-7 doi:10.1002/ajmg.a.37640.
PMID: 27028366
11
Apert syndrome: magnetic resonance imaging (MRI) of associated intracranial anomalies.
Tan AP, Mankad K
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2018; (34(2)):205-216 doi:10.1007/s00381-017-3670-0.
PMID: 29198073
12
Apert syndrome: A case report of prenatal ultrasound, postmortem cranial CT, and molecular genetic analysis.
Zhang W, Xue H, Huang D, et al.
Journal of clinical ultrasound : JCU 2021; (49(3)):250-253 doi:10.1002/jcu.22927.
PMID: 32954549
13
Apert syndrome with congenital diaphragmatic hernia: another case report and review of the literature.
Kaur R, Mishra P, Kumar S, et al.
Clinical dysmorphology 2019; (28(2)):78-80 doi:10.1097/MCD.0000000000000261.
PMID: 30672749
14
Successful reverse total shoulder replacement in a patient with Apert syndrome.
Burton C, Koong DP, Seagrave K, et al.
Shoulder & elbow 2024; (16(2)):169-172 doi:10.1177/17585732231207365.
PMID: 38655411
15
Paternal Age as a Contributing Factor in Apert Syndrome.
Raposo-Amaral CE, Zecchin KG, Denadai R, et al.
The Journal of craniofacial surgery 2020; (31(4)):1167 doi:10.1097/SCS.0000000000006451.
PMID: 32282485

This page explains the genetics of Apert syndrome for educational purposes. Your geneticist or pediatrician is the best source for interpreting your child's specific genetic testing report and risks.

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