Adams–Oliver syndrome

Adams–Oliver syndrome
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Synonyms	Congenital scalp defects with distal limb anomalies<ref> Orphanet: Adams Oliver syndrome(link). www.orpha.net. </ref>
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Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium (cutis aplasia congenita), transverse defects of the limbs, and mottling of the skin.

Signs and symptoms

Two key features of AOS are aplasia cutis congenita with or without underlying bony defects and terminal transverse limb defects.<ref>Mašek, Jan,

 The developmental biology of genetic Notch disorders, 
 Development, 
 
 Vol. 144(Issue: 10),
 pp. 1743–1763,
 DOI: 10.1242/dev.148007,
 PMID: 28512196,</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 cardiovascular malformations, cleft lip and/or palate, abnormal renal system, and neurologic disorders 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, portal sclerosis, arteriovenous malformations, abnormal umbilical veins, and dilated renal veins.

Genetics

AOS was initially described as having 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 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.

Six AOS genes have been identified: ARHGAP31,<ref>Southgate, Laura,

 Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies, 
 American Journal of Human Genetics, 
 
 Vol. 88(Issue: 5),
 pp. 574–585,
 DOI: 10.1016/j.ajhg.2011.04.013,
 PMID: 21565291,
 PMC: 3146732,</ref> DOCK6,<ref>Shaheen, Ranad, 
 Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome, 
 American Journal of Human Genetics, 
 
 Vol. 89(Issue: 2),
 pp. 328–333,
 DOI: 10.1016/j.ajhg.2011.07.009,
 PMID: 21820096,
 PMC: 3155174,</ref> RBPJ,<ref>Hassed, Susan J., 
 RBPJ mutations identified in two families affected by Adams-Oliver syndrome, 
 American Journal of Human Genetics, 
 
 Vol. 91(Issue: 2),
 pp. 391–395,
 DOI: 10.1016/j.ajhg.2012.07.005,
 PMID: 22883147,
 PMC: 3415535,</ref> EOGT,<ref name=":1">Shaheen, Ranad, 
 Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome, 
 American Journal of Human Genetics, 
 
 Vol. 92(Issue: 4),
 pp. 598–604,
 DOI: 10.1016/j.ajhg.2013.02.012,
 PMID: 23522784,
 PMC: 3617382,</ref><ref>Cohen, Idan, 
 Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase, 
 European Journal of Human Genetics, 
 
 Vol. 22(Issue: 3),
 pp. 374–378,
 DOI: 10.1038/ejhg.2013.159,
 PMID: 23860037,
 PMC: 3925282,</ref> NOTCH1,<ref>Stittrich, Anna-Barbara, 
 Mutations in NOTCH1 cause Adams-Oliver syndrome, 
 American Journal of Human Genetics, 
 
 Vol. 95(Issue: 3),
 pp. 275–284,
 DOI: 10.1016/j.ajhg.2014.07.011,
 PMID: 25132448,
 PMC: 4157158,</ref><ref>Southgate, Laura, 
 Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies, 
 Circulation: Cardiovascular Genetics, 
 
 Vol. 8(Issue: 4),
 pp. 572–581,
 DOI: 10.1161/CIRCGENETICS.115.001086,
 PMID: 25963545,
 PMC: 4545518,</ref> and DLL4.<ref>Meester, Josephina A. N., 
 Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome, 
 American Journal of Human Genetics, 
 
 Vol. 97(Issue: 3),
 pp. 475–482,
 DOI: 10.1016/j.ajhg.2015.07.015,
 PMID: 26299364,
 PMC: 4564989,</ref> ARHGAP31 and DOCK6 are both regulatory proteins that control members of the Rho family of GTPases and specifically regulate the activity of Cdc42 and 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.

RBPJ, EOGT, NOTCH1 and DLL4 are all involved in the 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.

Mechanism

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>Webster, William S.,

 The effect of hypoxia in development, 
 Birth Defects Research. Part C, Embryo Today: Reviews, 
 
 Vol. 81(Issue: 3),
 pp. 215–228,
 DOI: 10.1002/bdrc.20102,
 PMID: 17963271,</ref><ref>Ghatpande, Satish K., 
 Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos, 
 Birth Defects Research. Part A, Clinical and Molecular Teratology, 
 
 Vol. 82(Issue: 3),
 pp. 121–130,
 DOI: 10.1002/bdra.20438,
 PMID: 18186126,
 PMC: 3752680,</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.

In rare cases, AOS can be associated with chromosomal translocations. A panel of candidate genes (including ALX4, ALX1, MSX1, MSX2, P63, RUNX2 and HOXD13) were tested but no disease-causing mutations were identified.<ref>Verdyck, Pieter,

 Clinical and molecular analysis of nine families with Adams-Oliver syndrome, 
 European Journal of Human Genetics, 
 
 Vol. 11(Issue: 6),
 pp. 457–463,
 DOI: 10.1038/sj.ejhg.5200980,
 PMID: 12774039,</ref><ref>Verdyck, P., 
 Adams-Oliver syndrome: clinical description of a four-generation family and exclusion of five candidate genes, 
 Clinical Genetics, 
 
 Vol. 69(Issue: 1),
 pp. 86–92,
 DOI: 10.1111/j.1399-0004.2006.00552.x,
 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 a clinical diagnosis based on the specific features described above. A system of major and minor criteria was proposed.<ref>Snape, Katie M. G.,

 The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects, 
 American Journal of Medical Genetics Part A, 
 
 Vol. 149A(Issue: 8),
 pp. 1860–1881,
 DOI: 10.1002/ajmg.a.32708,
 PMID: 19610107,</ref>

Major features	Minor features
Terminal transverse limb defects	Cutis marmorata
Aplasia cutis congenita	Congenital heart defect
Family history of AOS	Vascular anomaly

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.

Management

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. ^{(March 2017)}

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. ^{(March 2017)}

Epidemiology

AOS is a rare genetic disorder and the annual incidence or overall prevalence of AOS is unknown. Approximately 100 individuals with this disorder have been reported in the medical literature.

History

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">Adams, Forrest H.,

 HEREDITARY DEFORMITIES IN MAN Due to Arrested Development, 
 Journal of Heredity, 
 
 Vol. 36(Issue: 1),
 pp. 3–7,
 DOI: 10.1093/oxfordjournals.jhered.a105415,</ref>

References

Kenneth L,

 Smith's Recognizable Patterns of Human Malformation, 
 5th edition, 
 Saunders, 
 1997, 
  
  
 ISBN 0-7216-6115-7,

William,

 Andrews' Diseases of the Skin: Clinical Dermatology, 
 10th edition, 
 Saunders, 
 2005, 
  
  
 ISBN 0-7216-2921-0,

,

 Adams–Oliver syndrome: Additions to the clinical features and possible role of BMP pathway., 
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 2009,
 Vol. 149(Issue: 8),
 pp. 1678–1684,
 DOI: 10.1002/ajmg.a.32938,
 PMID: 19606482,

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 Autosomal dominant inheritance of scalp defects with ectrodactyly, 
 Am J Med Genet, 
 1979,
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 Association of Adams–Oliver syndrome with pulmonary arterio-venous malformation in the same family: a further support to the vascular hypothesis., 
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 2005,
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 Adams–Oliver syndrome in siblings with central nervous system findings, epilepsy, and developmental delay: refining the features of a severe autosomal recessive variant., 
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,

 Adams–Oliver syndrome revisited, 
 Am J Med Genet, 
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 Congenital cardiac malformations in Adams–Oliver syndrome., 
 Clin Genet, 
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 Vol. 47(Issue: 2),
 pp. 80–84,
 DOI: 10.1111/j.1399-0004.1995.tb03928.x,
 PMID: 7606848,

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