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Apert syndrome: A dermatologist’s perspective
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How to cite this article: Kamra N, Tuknayat A. Apert syndrome: A dermatologist’s perspective. CosmoDerma 2021;1:66.
Abstract
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.
Keywords
Apert
Acrocephaly
Craniosynostoses
Acne
INTRODUCTION
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.
MATERIAL AND METHODS
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]
| 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 Brachycephaly |
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 |
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| 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 |
No | |||||
| 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 Scoliosis |
Acne Palmoplantar hyperhidrosis Plantar hyperkeratosis Nail dystrophy |
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| 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:
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Craniofacial abnormalities
Craniosynostosis
Turribrachycephaly with a high forehead
Asymmetric flat facies
Cloverleaf skull appearance
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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.
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Skeletal malformations
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Symmetrical syndactyly (mitten hand and sock foot/cloven or uncloven hoof)
Fusion of the second third and fourth fingers – Most common
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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.
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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.
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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]
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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.
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Otolaryngological anomalies
Small nose (occasionally parrot beak like)
Choanal atresia
Obstructive sleep apnea
Conductive hearing loss.
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Cardiovascular anomalies (10%)
Atrial and ventricular septal defects
Overriding aorta
Endocardial fibroelastosis.
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Renal anomalies
Hydronephrosis
Polycystic kidney
Hypernephrosis.
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Gastrointestinal anomalies
Esophageal atresia
Pyloric stenosis
Ectopic anus
Hernia.
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Respiratory
Pulmonary aplasia
Atrophy of pulmonary arteries
Anomalies of tracheal cartilage
Pulmonary stenosis.
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Genitourinary anomalies (9.6%)
Bicornuate uterus
Neurogenic bladder
Recurrent urinary tract infections.
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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.
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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.
CONCLUSION
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
Nil.
Conflicts of interest
There are no conflicts of interest.
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