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Review Article

Apert syndrome: A dermatologist’s perspective

Department of Dermatology, Kalpana Chawla Government Medical College, Karnal, Haryana, India
Corresponding author: Ankita Tuknayat, 50I3/1 Modern Housing Complex Manimajra, Chandigarh, India.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Kamra N, Tuknayat A. Apert syndrome: A dermatologist’s perspective. CosmoDerma 2021;1:66.


Apert syndrome is a Type 1 acrocephalosyndactyly syndrome presenting predominantly with craniofacial malformations and syndactyly. It can present with a multitude of clinical features involving any system of the body. A literature search of the PubMed electronic database was performed using the keywords “Apert syndrome” and “dermatology” in the title. The relevant references of the included articles were traced and included. A total of 27 articles appeared, the abstracts of which were screened and reviewed by both the authors independently for inclusion. After carefully analyzing all papers case by case, 21 such cases were retrieved. Cases presenting with other clinical features apart from dermatological features were also reviewed but were not included in the table. A total of about 30 patients of Apert syndrome have been described in dermatological literature, acne being the most common dermatological manifestation. Predominant clinical features in all the cases were brachycephaly due to craniosynostosis and syndactyly of hands and feet. Most of the patients had skeletal, dental, gastrointestinal, genitourinary, respiratory, cardiovascular, and dermatological manifestations in varying proportions. Apert syndrome is a rare entity which can present to a dermatologist. It is, therefore, pertinent to be able to diagnose and recognize the various clinical features of this syndrome to ensure timely management of such patients.




Apert syndrome was first described by Troquart, and later, a case series including nine patients were reported by a French physician, Eugene Apert in 1906 giving the syndrome its name.[1] It is a type 1 acrocephalosyndactyly syndrome having a prevalence of 15.5 per million live births.[2] The characteristic clinical features include acrocephalic (cone shaped) head, premature fusion of coronal sutures, facial dysmorphism, maxillary hypoplasia, and fusion of the digits.[3] There may be associated abnormalities of upper or lower respiratory tract, cardiovascular, genitourinary, and gastrointestinal system. Patients may also present with mental retardation.[3] Presentation with dermatological features like nodulocystic acne is rare.

A review of the PubMed electronic database and an extensive search of literature for systemic involvement in Apert syndrome have been done and an effort is being made to enlist all the clinical manifestations of this rare entity.


A literature search of the PubMed electronic database was performed using the keywords “Apert syndrome” and “dermatology” in the title. A total of 27 articles appeared, the abstracts of which were screened and reviewed by both the authors independently for inclusion. Cases presenting with other clinical features apart from dermatological features were also reviewed but were not included in the table.

After carefully analyzing all papers case by case, we were able to retrieve 21 such cases (complete references available on request to the corresponding author), which were re-evaluated, categorized, and outlined as a detailed chronological table. The relevant references of the included articles were also traced and included.

Apert syndrome

Apert syndrome is a type of craniosynostosis syndromes affecting the first branchial arch and is characterized by premature fusion of the sutures along with other systemic anomalies.[4]

Various etiological factors such as maternal viral infection, antenatal drug consumption, and high paternal age have been implicated for this rare syndrome.[5] It is caused due to a missense mutation (substitutions in amino acids Ser252Trp and Pro253Arg) in exon 7 of fibroblast growth factor receptor-2 (FGFR2) on chromosome 10q26. These amino acids are located in linking domains and two isoforms have been studied: (1) Bacterially expressed kinase is expressed on the embryonic skeleton and is responsible for the craniofacial alterations in Apert syndrome; (2) keratinocyte growth factor receptor is expressed in the embryonic epithelium and is responsible for syndactyly. KGF is also involved in differentiation and growth of the hair follicle and it induces increased activity of 5-alpha-reductase Type I in sebaceous glands of acne areas.[6]

Both FGFR2 isoforms (2a and 2b) of this pleiotropic gene are involved in cell proliferation, differentiation, migration, mesenchymal development, and survival in many different contexts including embryonic development, angiogenesis, and tooth morphogenesis. FGFR2b presents in the suprabasal spinous layer of the epidermis and sebocytes binds FGF 7 and 10, has an important role in epidermal differentiation. These FGFR2 mutations in synergy with IGF1 enhance downstream signaling of P13K/Akt pathway, leading to an end-organ hyper-responsiveness to androgen and this androgen-dependent overstimulation causes hyperproliferation and activation of infundibular keratinocytes and sebocytes and early fusion of epiphyses, leading to deformities of skull, hands, and feet. Apert osteoblasts exhibit increased expression of IL-1a and IL-1b.[6]

A total of about 30 patients of Apert syndrome have been described in dermatological literature [Table 1].[4-30] Most of the cases had sporadic mutation. Dermatological features were first described in seven out of nine patients by Solomon et al.[5] Predominant clinical features in all the cases were brachycephaly due to craniosynostosis and syndactyly of hands and feet. Most of the patients had multisystemic involvement and had skeletal, dental, gastrointestinal, genitourinary, respiratory, cardiovascular, nervous, otolaryngological, and dermatological manifestations in varying proportions.[8]

Table 1:: A chronological review of all the cases of Apert syndrome.
Author Year Inheritance Age of the patient Presenting clinical features Cutaneous features
Hermann et al., Solomon et al.[4,5] 1969 and 1970 Sporadic 9 patients
14 y/F
14 y/M
13 y/F
27 y/F
16 y/M
12 y/M
9 y/M
26 y/M
31 y/M
Craniofacial malformations Syndactyly of hands and feet Mental retardation in two patients
Conductive hearing loss in three patients Agenesis of corpus callosum in one patient
All seven post-pubertal patients showed moderate-to-severe acne on chest, back, face, arms, and forearms in varying distribution
Sohi and Sohi[15] 1980 Sporadic 1 y/F Congenital Syndactyly of toes and fingers Acrocephalic skull
Flat facies Exophthalmos Hypertelorism
Thickened first metacarpal forked at the base
Intracranial calcification
Greasy skin
Steffen[16] 1982 Mother had a history of a previous child with anencephaly and missing limb 15 y/M Craniosynostosis Proptosis
Depressed nasal bridge Midface hypoplasia Hypertelorism Syndactyly
Acneiform eruption on the whole skin sparing palms and soles
Robison and Wilms[11] 1989 Sporadic 20 y/M Facial dysmorphism Syndactyly
Acneiform eruption over chest, back, and arms
Parker et al.[17] 1992 Sporadic 15 y/M Syndactyly Brachycephaly
Facial dysmorphism
Acne on shoulder, chest, upper arms, and forearms
Henderson et al.[6] 1995 Sporadic 2 cases
1.16 y/F
2.18 y/F
Syndactyly involving the hands and feet Hypertelorism
Midface hypoplasia Proptosis
Severe cystic acne involving the face, back, chest, arms, and forearms
Downs et al.[18] 1999 Sporadic 11 y/M Craniofacial malformations Choanal atresia
Syndactyly (atypical form – only soft-tissue fusion)
Cleft palate
Mild mental retardation
Reduced shoulder and elbow movement Obstructive sleep apnea
Pustular acne over face, upper torso, arms, and thighs
Greasy skin and hair
Gilaberte et al.[19] 2003 Sporadic 13 y/M Craniosynostosis
Syndactyly of hands and feet
Pustular and cystic acne on face, trunk, arms, and thighs
Cuerda et al.[7] 2003 Sporadic 12 y/M Craniosynostosis Syndactyly of hands and feet Epilepsy Cysts and pustular lesions located on the arms, upper chest, and back, without involvement of the face, as well as hyperhidrosis of the palms and soles
Mukhopadhyay et al.[20] 2004 Sporadic 2 m/F Facial dysmorphism Low posterior hairline High-arched palate Syndactyly Hydrocephalus
Atrophy of frontal and parietal lobes Bifurcation of first metatarsal base
Epigastric hernia
Acneiform lesions on the nose
Verma and Draznin[21] 2005 Sporadic 10 y/M Symmetric syndactyly of all digits of the hands and feet
Midface hypoplasia Exophthalmia ocular Hypertelorism
Cleft palate
Hyperhidrosis of feet Synonychia Onychomycosis
Benjamin et al.[22] 2005 Autosomal dominant Twins 13 y/M Facial dysmorphism Syndactyly Brachycephaly
Twin A – aortic stenosis, asthma, ventricular septal defect
Twin B – omphalocele, coarctation of aorta
Twin A – Stage 4 acne Twin B – Stage 3 acne
Hsieh and Ho[13] 2005 Sporadic 15 y/F Midface hypoplasia Brachycephaly Syndactyly Severe acne on face, chest, back, abdomen, and forearms
Freiman et al.[23] 2006 Sporadic 14 y/M Brachycephalic Broad nose with bulbous tip
Hypertelorism. Bilateral symmetrical syndactyly of both his hands and feet
Hyperkeratosis on the lateral plantar aspects mild acneiform papules on the face and upper extremities
Tiwari et al.[24] 2007 Sporadic 20 y/F Symmetrical syndactyly of all the digits of the hands and feet
Progressive loss of vision in the right eye Short stature
Midface hypoplasia Exophthalmia of the right eye
Corneal opacity in the right eye Ocular hypertelorism Subnormal intelligence
Septo-optic dysplasia Corneal opacity Phthisis bulbi
Agenesis of the septum pellucidum
Synonychia Onychomycosis
DeGiovanni et al.[25] 2007 sporadic 13 y/F Dysmorphic facies Brachycephaly Exophthalmos Depressed nasal septum
Symmetrical syndactyly of the index-middle fingers and all toes
Physical and developmental delay CT head scan showed Dandy-Walker variant
Moderate pustular acne was seen on the forearms and back of the trunk
De et al.[26] 2008 Sporadic 8 m/M Syndactyly of all four limbs Brachycephaly
Frontal bossing
Midface hypoplasia, depressed nasal bridge Upward slanting of the eyes
Low-set ears
Growth and mental retardation
Dolenc-Voljč and Finžgar-Perme[27] 2008 Sporadic 14 y/M Brachycephaly Syndactyly
Facial dysmorphism
On initial presentation, numerous comedones, papules, pustules, and nodular acne lesions were seen on the face, neck, chest, and back, extending to the upper arms, forearms, thighs, and shanks
Paradisi et al.[28] 2011 Sporadic 15 y/M Brachycephaly Hypertelorism Mandibular prognathism
Parrot beak nose Cutaneous and osseous syndactyly of hands
Papulopustular and nodular lesions on the face
Bissacotti et al.[29] 2016 Sporadic 15 y/F Acrocephaly hypertelorism proptosis Strabismus
Interrupted eyebrows
Maxillary hypoplasia Mandibular overjet Malocclusion Misalignment and crowding of the teeth Symmetric syndactyly of the hands and feet
Palmoplantar hyperhidrosis Plantar hyperkeratosis
Nail dystrophy
Langenderfer et al.[30] 2019 Sporadic 37 y/M Craniosynostosis Neurogenic bladder Bilateral hearing loss Migraines
Flat forehead Midface Syndactyly Hypertelorism Neurogenic bladder
Inflammatory and nodulocystic acne involving the face, chest, and back

Based on this review, we enumerate the various clinical features of Apert syndrome as under:

  1. Craniofacial abnormalities

    • Craniosynostosis

    • Turribrachycephaly with a high forehead

    • Asymmetric flat facies

    • Cloverleaf skull appearance

    • Midfacial malformations

      • Pseudoprognathic appearance due to maxillary retroposition

      • Frontal bossing

    • Large and low set ears

    • Trapezoid lips – upper lip is lifted in the midline.

    • Shallow orbits with proptosis

    • Increased digital markings found on interior of skull.

  2. Skeletal malformations

    • Symmetrical syndactyly (mitten hand and sock foot/cloven or uncloven hoof)

      • Fusion of the second third and fourth fingers – Most common

      • Severity of the syndactyly scored as: [8]

        • Type I: Thumb and part of fifth finger are separate from syndactylous mass

        • Type II: Little fingers are not separate

        • Type III: Thumb and all fingers are included.

      • Bifurcation of first metatarsal base

    • Lobster claw deformity

    • Short humerus

    • Synostosis of radius and humerus

    • Flat radial head

    • Short or absent neck of scapula

    • Small capitulum

    • Shortened upper limb length relative to body length

    • Fusion of vertebra

    • Deformities of hip joint

    • Diastasis of symphysis pubis

    • Limitation of joint mobility (glenohumeral joint and elbow joint)

    • Ankylosis of elbows, shoulder, and hips

    • Scoliosis

    • Lumbar lordosis.

  3. Orodental abnormalities

    • Delayed eruption of teeth – mean dental developmental delay of 0.96 years (range of 0.5– 2.9 years)

    • Crowding of teeth within the alveolus

    • Supernumerary teeth

    • Congenitally missing teeth

    • Malocclusion

    • Thick gingiva

    • Shovel-shaped incisors[9]

    • Bilateral crossbite

    • Mandibular overjet

    • Midline deviation

    • Narrow palate

    • Cleft palate or bifid uvula – 75% of the cases

    • Reduction in the size of the maxilla

    • Anterior open bite of the maxilla

    • Speech and articulation defects/hyper-resonant due to malocclusion[10]

    • Arched hard palate with bilateral swellings of the palatine processes, resulting in a pseudocleft in the midline.

    • Low postured and protruded tongue.

  4. Dermatological

    • Broad, short fused nails (synonychia) with micronychia

    • Brittle nails

    • Acne – starting from the age of 9–12 years

    • Pigmentary dilution of skin and hair

    • Hyperhidrosis

    • Oculocutaneous albinism

    • Interrupted eyebrows

    • Forehead wrinkling

    • Paronychial infections

    • Skin dimpling over the knuckles, shoulders, and elbows

    • Lateral plantar hyperkeratosis.[28]

  5. Ophthalmological

    • Pigmentary dilution of eyes

    • Hypertelorism

    • Divergent squint

    • Optic atrophy

    • Phthisis bulbi

    • Optic nerve hypoplasia

    • Keratoconus

    • Hyperopic eyes

    • Proptosis

    • Errors of refraction

    • Exposure keratitis

    • Blindness.

  6. Otolaryngological anomalies

    • Small nose (occasionally parrot beak like)

    • Choanal atresia

    • Obstructive sleep apnea

    • Conductive hearing loss.

  7. Cardiovascular anomalies (10%)

    • Atrial and ventricular septal defects

    • Overriding aorta

    • Endocardial fibroelastosis.

  8. Renal anomalies

    • Hydronephrosis

    • Polycystic kidney

    • Hypernephrosis.

  9. Gastrointestinal anomalies

    • Esophageal atresia

    • Pyloric stenosis

    • Ectopic anus

    • Hernia.

  10. Respiratory

    • Pulmonary aplasia

    • Atrophy of pulmonary arteries

    • Anomalies of tracheal cartilage

    • Pulmonary stenosis.

  11. Genitourinary anomalies (9.6%)

    • Bicornuate uterus

    • Neurogenic bladder

    • Recurrent urinary tract infections.

  12. Central nervous system anomalies

    • Agenesis of corpus callosum

    • Megalencephaly

    • Gyral abnormalities

    • Encephalocele

    • Pyramidal tract abnormalities

    • Hypoplasia of cerebral white matter

    • Heterotopic gray matter

    • Hypoplasia or absence of the septum pellucidum

    • Hippocampal hypoplasia or dysplasia

    • Ventriculomegaly

    • Cavum vergae.

  13. Psychological problems

    • Mental retardation

    • Antisocial behavior.

Among the dermatological manifestations, acne is the most prominent feature. It usually starts at the age of 9–12 years.[11] The acne in this syndrome is severe, inflammatory or comedonal, located at face, chest, back, as well as unusual sites such as arms, forearms, buttocks, and thighs and they are recalcitrant to treatment. Munro’s acne nevus, a mosaic cutaneous manifestation of Apert syndrome, has also been studied and it is characterized by sharply bordered acneiform lesions along the lines of Blaschko.[12]

The pathogenesis of acne is similar, that is, involving the FGFR2 and causing sebaceous hyperplasia due to end-organ hypersensitivity to androgen.[12] Various treatment options for acne have been tried including multiple oral and topical antibiotics and azelaic acid. It has been observed that isotretinoin in a dose of 1–2 mg/kg/day has the maximum benefit in such patients as it is involved in downregulating FGFR2 signaling. Recently, oral contraceptive pills have also been tried in the treatment of acne in Apert syndrome.[13] Isotretinoin is usually started at a higher dose in such patients and majority of patients remain clear of acne for months. However, some relapses may occur, requiring repeated dosing. It carries the risk of serious side effects such as hyperostosis and pseudotumor cerebri, thus risk-benefit ratio should be assessed in treating such patients.

Other craniosynostosis syndromes involving the same FGFR 2 gene may be considered in the differential diagnosis of Apert syndrome. Almost 70 such syndromes have been studied including Crouzon syndrome, Pfeiffer syndrome, and JacksonWeiss syndrome. Crouzon syndrome has normal hands and feet as well as normal intelligence. When fusions are present, C5–C6 involvement in the Apert syndrome and C2–C3 involvement in Crouzon syndrome separate the two conditions in most cases. Acanthosis nigricans is a dermatologic association with Crouzon syndrome.[3]

The presence of broad and medially deviated thumbs and halluces in association with cutaneous syndactyly differentiates Pfeiffer syndrome from Apert syndrome. Cutaneous hypopigmentation can also be associated with Pfeiffer syndrome.[4]

Other syndromes presenting with dysmorphic features and bony abnormalities like Carpenter syndrome can be kept as a differential diagnosis.[4] This Ras-related protein (RAB23) craniosynostosis characteristically has brachydactyly, syndactyly, aplasia, or hypoplasia of the hands and/or polydactyly of the feet. It is characterized by hypogenitalism or obesity which is not a feature of Apert syndrome.

Saethre-Chotzen syndrome, also known as acrocephalosyndactyly Type 3, has craniosynsostosis, ptosis, partial syndactyly, and hearing loss but most patients have normal intelligence. It has a mutation in TWIST1 gene on chromosome 7p21.[14]

Patients with Apert syndrome require multidisciplinary approach to management. Neurosurgeons, plastic surgeons, otorhinolaryngologists, orthodontists, ophthalmologists, radiologists, geneticists, pediatricians, and dermatologists must all work in concert to care for such patients. Early surgical intervention is imperative for optimal outcomes. Subsequent treatment should be tailored to each individual patient’s needs.


Apert syndrome is a rare entity which can present to a dermatologist. It is, therefore, pertinent to be able to diagnose and recognize the various clinical features of this syndrome to ensure timely management of such patients.

Declaration of patient consent

Patient’s consent not required as patients identity is not disclosed or compromised.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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