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{{Infobox medical condition (new)
{{Infobox medical condition
| name = Adams–Oliver syndrome
| name = Adams–Oliver syndrome
| image =
| synonyms = AOS
| caption =
| pronunciation =
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| image =
| pronounce =
| alt =
| field =
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| synonyms = Congenital scalp defects with distal limb anomalies<ref>{{cite web |last1=RESERVED |first1=INSERM US14-- ALL RIGHTS |title=Orphanet: Adams Oliver syndrome |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=974 |website=www.orpha.net |accessdate=16 May 2019 |language=en}}</ref>
'''Adams–Oliver syndrome''' ('''AOS''') is a rare [[congenital disorder]] characterized by defects of the [[scalp]] and [[Human cranium|cranium]] (cutis aplasia congenita), transverse defects of the limbs, and [[cutis marmorata telangiectatica congenita|mottling of the skin]].
'''Adams–Oliver Syndrome''' ('''AOS''') is a rare congenital disorder characterized by defects of the scalp and cranium (aplasia cutis congenita), transverse limb defects, and mottled skin appearance. First described in 1945 by Dr. Forrest H. Adams and Dr. Clarence Paul Oliver, AOS presents with a spectrum of clinical features that can vary significantly among affected individuals.
=== Epidemiology ===
== Signs and symptoms ==
AOS is an uncommon condition, with an estimated incidence of approximately 1 in 225,000 live births. It affects individuals of all genders and ethnic backgrounds equally. Due to its rarity, precise prevalence data are limited.
Two key features of AOS are aplasia cutis congenita with or without underlying bony defects and terminal transverse limb defects.<ref>{{Cite journal|last=Mašek|first=Jan|last2=Andersson|first2=Emma R.|date=2017-05-15|title=The developmental biology of genetic Notch disorders|journal=Development|language=en|volume=144|issue=10|pages=1743–1763|doi=10.1242/dev.148007|issn=0950-1991|pmid=28512196|doi-access=free}}</ref> Cutis aplasia congenita is defined as missing skin over any area of the body at birth; in AOS skin aplasia occurs at the vertex of the skull. The size of the lesion is variable and may range from solitary round hairless patches to complete exposure of the cranial contents. There are also varying degrees of terminal limb defects (for example, shortened digits) of the upper extremities, lower extremities, or both. Individuals with AOS may have mild growth deficiency, with height in the low-normal percentiles. The skin is frequently observed to have a mottled appearance ([[cutis marmorata telangiectatica congenita]]). Other congenital anomalies, including [[congenital heart defect|cardiovascular malformations]], [[cleft lip and palate|cleft lip and/or palate]], abnormal [[renal system]], and [[neurologic disorder]]s manifesting as seizure disorders and developmental delay are sometimes observed. Variable defects in blood vessels have been described, including hypoplastic [[aortic arch]], [[middle cerebral artery]], [[pulmonary arteries]]. Other vascular abnormalities described in AOS include absent [[portal vein]], [[hepatic portal system|portal sclerosis]], [[arteriovenous malformations]], abnormal [[umbilical vein]]s, and dilated [[renal vein]]s.
== Clinical Features and Diagnosis ==
=== Major Clinical Features ===
== Genetics ==
* 1. '''Aplasia Cutis Congenita (ACC):''' Congenital absence of skin, typically on the scalp vertex, leading to localized areas devoid of skin and, in severe cases, underlying bone.
AOS was initially described as having [[Dominance (genetics)|autosomal dominant]] inheritance due to the reports of families with multiple affected family members in more than one generation.<ref name=":0" /> The severity of the condition can vary between family members, suggestive of variable [[expressivity (genetics)|expressivity]] and reduced [[penetrance]] of the disease-causing [[allele]]. Subsequently, it was reported that some cases of AOS appear to have [[autosomal recessive]] inheritance, perhaps with somewhat more severe phenotypic effects.
* 2. '''Limb Malformations:''' These may include:
** '''Syndactyly:''' Fusion of fingers or toes.
Six AOS genes have been identified: [[ARHGAP31]],<ref>{{Cite journal|last=Southgate|first=Laura|last2=Machado|first2=Rajiv D.|last3=Snape|first3=Katie M.|last4=Primeau|first4=Martin|last5=Dafou|first5=Dimitra|last6=Ruddy|first6=Deborah M.|last7=Branney|first7=Peter A.|last8=Fisher|first8=Malcolm|last9=Lee|first9=Grace J.|date=2011-05-13|title=Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies|journal=American Journal of Human Genetics|volume=88|issue=5|pages=574–585|doi=10.1016/j.ajhg.2011.04.013|issn=1537-6605|pmc=3146732|pmid=21565291}}</ref> [[DOCK6]],<ref>{{Cite journal|last=Shaheen|first=Ranad|last2=Faqeih|first2=Eissa|last3=Sunker|first3=Asma|last4=Morsy|first4=Heba|last5=Al-Sheddi|first5=Tarfa|last6=Shamseldin|first6=Hanan E.|last7=Adly|first7=Nouran|last8=Hashem|first8=Mais|last9=Alkuraya|first9=Fowzan S.|date=2011-08-12|title=Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome|journal=American Journal of Human Genetics|volume=89|issue=2|pages=328–333|doi=10.1016/j.ajhg.2011.07.009|issn=1537-6605|pmc=3155174|pmid=21820096}}</ref> [[RBPJ]],<ref>{{Cite journal|last=Hassed|first=Susan J.|last2=Wiley|first2=Graham B.|last3=Wang|first3=Shaofeng|last4=Lee|first4=Ji-Yun|last5=Li|first5=Shibo|last6=Xu|first6=Weihong|last7=Zhao|first7=Zhizhuang J.|last8=Mulvihill|first8=John J.|last9=Robertson|first9=James|date=2012-08-10|title=RBPJ mutations identified in two families affected by Adams-Oliver syndrome|journal=American Journal of Human Genetics|volume=91|issue=2|pages=391–395|doi=10.1016/j.ajhg.2012.07.005|issn=1537-6605|pmc=3415535|pmid=22883147}}</ref> EOGT,<ref name=":1">{{Cite journal|last=Shaheen|first=Ranad|last2=Aglan|first2=Mona|last3=Keppler-Noreuil|first3=Kim|last4=Faqeih|first4=Eissa|last5=Ansari|first5=Shinu|last6=Horton|first6=Kim|last7=Ashour|first7=Adel|last8=Zaki|first8=Maha S.|last9=Al-Zahrani|first9=Fatema|date=2013-04-04|title=Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome|journal=American Journal of Human Genetics|volume=92|issue=4|pages=598–604|doi=10.1016/j.ajhg.2013.02.012|issn=1537-6605|pmc=3617382|pmid=23522784}}</ref><ref>{{Cite journal|last=Cohen|first=Idan|last2=Silberstein|first2=Eldad|last3=Perez|first3=Yonatan|last4=Landau|first4=Daniella|last5=Elbedour|first5=Khalil|last6=Langer|first6=Yshaia|last7=Kadir|first7=Rotem|last8=Volodarsky|first8=Michael|last9=Sivan|first9=Sara|date=2014-03-01|title=Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase|journal=European Journal of Human Genetics|volume=22|issue=3|pages=374–378|doi=10.1038/ejhg.2013.159|issn=1476-5438|pmc=3925282|pmid=23860037}}</ref> [[Notch 1|NOTCH1]],<ref>{{Cite journal|last=Stittrich|first=Anna-Barbara|last2=Lehman|first2=Anna|last3=Bodian|first3=Dale L.|last4=Ashworth|first4=Justin|last5=Zong|first5=Zheyuan|last6=Li|first6=Hong|last7=Lam|first7=Patricia|last8=Khromykh|first8=Alina|last9=Iyer|first9=Ramaswamy K.|date=2014-09-04|title=Mutations in NOTCH1 cause Adams-Oliver syndrome|journal=American Journal of Human Genetics|volume=95|issue=3|pages=275–284|doi=10.1016/j.ajhg.2014.07.011|issn=1537-6605|pmc=4157158|pmid=25132448}}</ref><ref>{{Cite journal|last=Southgate|first=Laura|last2=Sukalo|first2=Maja|last3=Karountzos|first3=Anastasios S. V.|last4=Taylor|first4=Edward J.|last5=Collinson|first5=Claire S.|last6=Ruddy|first6=Deborah|last7=Snape|first7=Katie M.|last8=Dallapiccola|first8=Bruno|last9=Tolmie|first9=John L.|date=2015-08-01|title=Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies|journal=Circulation: Cardiovascular Genetics|volume=8|issue=4|pages=572–581|doi=10.1161/CIRCGENETICS.115.001086|issn=1942-3268|pmc=4545518|pmid=25963545}}</ref> and [[DLL4]].<ref>{{Cite journal|last=Meester|first=Josephina A. N.|last2=Southgate|first2=Laura|last3=Stittrich|first3=Anna-Barbara|last4=Venselaar|first4=Hanka|last5=Beekmans|first5=Sander J. A.|last6=den Hollander|first6=Nicolette|last7=Bijlsma|first7=Emilia K.|last8=Helderman-van den Enden|first8=Appolonia|last9=Verheij|first9=Joke B. G. M.|date=2015-09-03|title=Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome|journal=American Journal of Human Genetics|volume=97|issue=3|pages=475–482|doi=10.1016/j.ajhg.2015.07.015|issn=1537-6605|pmc=4564989|pmid=26299364}}</ref> ARHGAP31 and DOCK6 are both regulatory proteins that control members of the [[Rho family of GTPases]] and specifically regulate the activity of [[CDC42|Cdc42]] and [[RAC1|Rac1]]. Autosomal dominant mutations in ARHGAP31 (a [[GTPase-activating protein]]) and autosomal recessive mutations in DOCK6 (a [[guanine nucleotide exchange factor]]) cause an accumulation of the inactive GTPase and lead to defects of the [[cytoskeleton]].
** '''Brachydactyly:''' Shortened digits.
** '''Oligodactyly:''' Missing fingers or toes.
RBPJ, EOGT, NOTCH1 and DLL4 are all involved in the [[Notch signaling pathway|Notch signalling pathway]]. Mutations in EOGT are found in AOS with autosomal recessive inheritance;<ref name=":1" /> the other three genes account for cases with autosomal dominant inheritance.
** '''Hypoplastic or Absent Nails:''' Underdeveloped or missing nails.
=== Minor Clinical Features ===
== Mechanism ==
* '''Cutis Marmorata Telangiectatica Congenita (CMTC):''' A vascular anomaly presenting as a reddish or purplish net-like pattern on the skin.
The precise mechanism underlying the congenital abnormalities observed in AOS is unknown. Similar terminal transverse limb anomalies and cardiovascular malformations are seen in animal models of hypoxic insults during the first trimester.<ref>{{Cite journal|last=Webster|first=William S.|last2=Abela|first2=Dominique|date=2007-09-01|title=The effect of hypoxia in development|journal=Birth Defects Research. Part C, Embryo Today: Reviews|volume=81|issue=3|pages=215–228|doi=10.1002/bdrc.20102|issn=1542-975X|pmid=17963271}}</ref><ref>{{Cite journal|last=Ghatpande|first=Satish K.|last2=Billington|first2=Charles J.|last3=Rivkees|first3=Scott A.|last4=Wendler|first4=Christopher C.|date=2008-03-01|title=Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos|journal=Birth Defects Research. Part A, Clinical and Molecular Teratology|volume=82|issue=3|pages=121–130|doi=10.1002/bdra.20438|issn=1542-0760|pmc=3752680|pmid=18186126}}</ref> Combined with the common association of cardiac and vascular abnormalities in AOS, it has been hypothesized that the spectrum of defects observed in AOS could be due to a disorder of [[vasculogenesis]].
* '''Congenital Heart Defects:''' Structural anomalies of the heart present at birth.
* '''Vascular Anomalies:''' Including abnormalities in blood vessels, which can lead to complications such as pulmonary hypertension.
In rare cases, AOS can be associated with [[chromosomal translocation]]s. A panel of [[candidate gene]]s (including [[ALX4]], [[ALX1]], [[MSX1]], [[MSX2]], [[TP73L|P63]], [[RUNX2]] and [[HOXD13]]) were tested but no disease-causing mutations were identified.<ref>{{Cite journal|last=Verdyck|first=Pieter|last2=Holder-Espinasse|first2=Muriel|last3=Hul|first3=Wim Van|last4=Wuyts|first4=Wim|date=2003-06-01|title=Clinical and molecular analysis of nine families with Adams-Oliver syndrome|journal=European Journal of Human Genetics|volume=11|issue=6|pages=457–463|doi=10.1038/sj.ejhg.5200980|issn=1018-4813|pmid=12774039|doi-access=free}}</ref><ref>{{Cite journal|last=Verdyck|first=P.|last2=Blaumeiser|first2=B.|last3=Holder-Espinasse|first3=M.|last4=Van Hul|first4=W.|last5=Wuyts|first5=W.|date=2006-01-01|title=Adams-Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes|journal=Clinical Genetics|volume=69|issue=1|pages=86–92|doi=10.1111/j.1399-0004.2006.00552.x|issn=0009-9163|pmid=16451141}}</ref> More recently, mutations in six genes have been identified, highlighting the Rho family of GTPases and the Notch signalling pathway as important factors in the pathogenesis of AOS.
=== Diagnosis ===
The diagnosis of AOS is primarily clinical, based on the presence of characteristic features. A proposed diagnostic criterion includes:
== Diagnosis ==
* '''Major Criteria:'''
The diagnosis of AOS is a clinical diagnosis based on the specific features described above. A system of major and minor criteria was proposed.<ref>{{Cite journal|last=Snape|first=Katie M. G.|last2=Ruddy|first2=Deborah|last3=Zenker|first3=Martin|last4=Wuyts|first4=Wim|last5=Whiteford|first5=Margo|last6=Johnson|first6=Diana|last7=Lam|first7=Wayne|last8=Trembath|first8=Richard C.|date=2009-08-01|title=The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects|journal=American Journal of Medical Genetics Part A|volume=149A|issue=8|pages=1860–1881|doi=10.1002/ajmg.a.32708|issn=1552-4833|pmid=19610107}}</ref>
* Terminal transverse limb defects.
{| class="wikitable"
* Aplasia cutis congenita.
|-
* Family history of AOS.
! Major features
'''Minor Criteria:'''
! Minor features
* Cutis marmorata.
|-
* Congenital heart defect.
| Terminal transverse limb defects
* Vascular anomaly.
| Cutis marmorata
A diagnosis is considered definitive with the presence of two major criteria or one major and one minor criterion. Genetic testing can identify mutations in known associated genes, aiding in diagnosis, especially in atypical cases.
|-
== Genetic Basis and Pathophysiology ==
| Aplasia cutis congenita
AOS exhibits genetic heterogeneity with both autosomal dominant and autosomal recessive inheritance patterns. Mutations in several genes have been implicated:
| Congenital heart defect
* '''ARHGAP31:''' Encodes a GTPase-activating protein involved in cytoskeletal organization.
|-
* '''DOCK6:''' Functions as a guanine nucleotide exchange factor, regulating actin cytoskeleton dynamics.
| Family history of AOS
* '''RBPJ, EOGT, NOTCH1, DLL4:''' These genes are components of the Notch signaling pathway, crucial for vascular development and cellular differentiation.
| Vascular anomaly
Disruptions in these genes affect vascular development and integrity, leading to the diverse manifestations of AOS.
|}
== Management and Prognosis ==
=== Management ===
The combination of two major criteria would be sufficient for the diagnosis of AOS, while a combination of one major and one minor feature would be suggestive of AOS. Genetic testing can be performed to test for the presence of mutation in one of the known genes, but these so far only account for an estimated 50% of patients with AOS. A definitive diagnosis may therefore not be achieved in all cases.
Treatment is symptomatic and multidisciplinary:
* '''Scalp Defects:''' Management ranges from conservative care with dressings to surgical interventions like skin grafting, depending on severity.
== Management ==
* '''Limb Anomalies:''' Orthopedic interventions, including prosthetics or corrective surgeries, aim to improve function and appearance.
Management of AOS is largely symptomatic and aimed at treating the various congenital anomalies present in the individual. When the scalp and/or cranial bone defects are severe, early surgical intervention with grafting is indicated.{{citation needed|date=March 2017}}
* '''Cardiac and Vascular Issues:''' Regular monitoring and appropriate medical or surgical treatments are essential for congenital heart defects and vascular anomalies.
Genetic counseling is recommended for affected families to discuss inheritance patterns, recurrence risks, and family planning options.
== Prognosis ==
=== Prognosis ===
The overall prognosis is excellent in most cases. Most children with Adams–Oliver syndrome can likely expect to have a normal life span. However, individuals with more severe scalp and cranial defects may experience complications such as hemorrhage and [[meningitis]], leading to long-term disability.{{citation needed|date=March 2017}}
The prognosis for individuals with AOS varies based on the severity of manifestations. While many lead normal lives with appropriate management, severe cases involving significant cardiac or vascular anomalies may have increased morbidity and mortality risks. Early detection and a tailored, multidisciplinary approach are crucial for optimizing outcomes.
== See Also ==
== Epidemiology ==
* '''[[Aplasia cutis congenita]]'''
AOS is a rare genetic disorder and the annual [[Incidence (epidemiology)|incidence]] or overall [[prevalence]] of AOS is unknown. Approximately 100 individuals with this disorder have been reported in the medical literature.
AOS was first reported by the American pediatric cardiologist Forrest H. Adams and the clinical geneticist Clarence Paul Oliver in a family with eight affected members.<ref name=":0">{{Cite journal|last=Adams|first=Forrest H.|last2=Oliver|first2=C. P.|date=1945-01-01|title=HEREDITARY DEFORMITIES IN MAN Due to Arrested Development|journal=Journal of Heredity|language=en|volume=36|issue=1|pages=3–7|issn=0022-1503|doi=10.1093/oxfordjournals.jhered.a105415}}</ref>
* '''[[Notch signaling pathway]]'''
== Citations ==
{{Reflist}}
== References ==
{{cite book |last = Jones |first = Kenneth L |title = Smith's Recognizable Patterns of Human Malformation |edition= 5th |publisher = Saunders |year = 1997 |isbn = 0-7216-6115-7}}
{{cite book |last = James |first = William |author2= Berger, Timothy|author3= Elston, Dirk |title = Andrews' Diseases of the Skin: Clinical Dermatology |edition= 10th |publisher = Saunders |year = 2005 |isbn = 0-7216-2921-0}}
{{cite journal |vauthors=Baskar S, Kulkarni ML, Kulkarni AM, Vittalrao S, Kulkarni PM |title=Adams–Oliver syndrome: Additions to the clinical features and possible role of BMP pathway. |journal=Am J Med Genet A |volume=149 |issue=8 |pages=1678–1684 |pmid=19606482 |year=2009 |doi=10.1002/ajmg.a.32938}}
{{cite journal |pmid=474617 |year=1979 |vauthors=Bonafede RP, Beighton P |title=Autosomal dominant inheritance of scalp defects with ectrodactyly |volume=3 |issue=1 |pages=35–41 |doi=10.1002/ajmg.1320030109 |journal=Am J Med Genet}}
{{cite journal |vauthors=Maniscalco M, Zedda A, Faraone S, de Laurentiis G, Verde R, Molese V, Lapiccirella G, Sofia M |title=Association of Adams–Oliver syndrome with pulmonary arterio-venous malformation in the same family: a further support to the vascular hypothesis. |journal=Am J Med Genet A |volume=136 |issue=3 |pages=269–274 |year=2005 |pmid=15948197 |doi=10.1002/ajmg.a.30828}}
{{cite journal |vauthors=McGoey RR, Lacassie Y |title=Adams–Oliver syndrome in siblings with central nervous system findings, epilepsy, and developmental delay: refining the features of a severe autosomal recessive variant. |journal=Am J Med Genet A |volume=146 |issue=4 |pages=488–491 |year=2008 |pmid=18203152 |doi=10.1002/ajmg.a.32163}}
Adams–Oliver Syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium (aplasia cutis congenita), transverse limb defects, and mottled skin appearance. First described in 1945 by Dr. Forrest H. Adams and Dr. Clarence Paul Oliver, AOS presents with a spectrum of clinical features that can vary significantly among affected individuals.
AOS is an uncommon condition, with an estimated incidence of approximately 1 in 225,000 live births. It affects individuals of all genders and ethnic backgrounds equally. Due to its rarity, precise prevalence data are limited.
1. Aplasia Cutis Congenita (ACC): Congenital absence of skin, typically on the scalp vertex, leading to localized areas devoid of skin and, in severe cases, underlying bone.
2. Limb Malformations: These may include:
Syndactyly: Fusion of fingers or toes.
Brachydactyly: Shortened digits.
Oligodactyly: Missing fingers or toes.
Hypoplastic or Absent Nails: Underdeveloped or missing nails.
The diagnosis of AOS is primarily clinical, based on the presence of characteristic features. A proposed diagnostic criterion includes:
Major Criteria:
Terminal transverse limb defects.
Aplasia cutis congenita.
Family history of AOS.
Minor Criteria:
Cutis marmorata.
Congenital heart defect.
Vascular anomaly.
A diagnosis is considered definitive with the presence of two major criteria or one major and one minor criterion. Genetic testing can identify mutations in known associated genes, aiding in diagnosis, especially in atypical cases.
AOS exhibits genetic heterogeneity with both autosomal dominant and autosomal recessive inheritance patterns. Mutations in several genes have been implicated:
ARHGAP31: Encodes a GTPase-activating protein involved in cytoskeletal organization.
DOCK6: Functions as a guanine nucleotide exchange factor, regulating actin cytoskeleton dynamics.
RBPJ, EOGT, NOTCH1, DLL4: These genes are components of the Notch signaling pathway, crucial for vascular development and cellular differentiation.
Disruptions in these genes affect vascular development and integrity, leading to the diverse manifestations of AOS.
Scalp Defects: Management ranges from conservative care with dressings to surgical interventions like skin grafting, depending on severity.
Limb Anomalies: Orthopedic interventions, including prosthetics or corrective surgeries, aim to improve function and appearance.
Cardiac and Vascular Issues: Regular monitoring and appropriate medical or surgical treatments are essential for congenital heart defects and vascular anomalies.
Genetic counseling is recommended for affected families to discuss inheritance patterns, recurrence risks, and family planning options.
The prognosis for individuals with AOS varies based on the severity of manifestations. While many lead normal lives with appropriate management, severe cases involving significant cardiac or vascular anomalies may have increased morbidity and mortality risks. Early detection and a tailored, multidisciplinary approach are crucial for optimizing outcomes.
