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Adams-Oliver syndrome 3(AOS3)

MedGen UID:: 766662
•Concept ID:: C3553748
•: Disease or Syndrome

Synonym:	AOS3

Gene (location): Gene(s) directly associated with this condition or phenotype.	RBPJ (4p15.2)

Monarch Initiative:	MONDO:0013895
OMIM®:	614814

Definition

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Additional descriptions

From OMIM
Hassed et al. (2012) described an autosomal dominant form of Adams-Oliver syndrome involving characteristic vertex scalp defects and terminal limb defects, but without congenital heart defects, other associated defects, or immune defects. For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300). http://www.omim.org/entry/614814

From MedlinePlus Genetics
Adams-Oliver syndrome is a rare condition that is present at birth. The primary features are an abnormality in skin development (called aplasia cutis congenita) and malformations of the limbs. A variety of other features can occur in people with Adams-Oliver syndrome.

Most people with Adams-Oliver syndrome have aplasia cutis congenita, a condition characterized by localized areas of missing skin typically occurring on the top of the head (the skull vertex). In some cases, the bone under the skin is also underdeveloped. Individuals with this condition commonly have scarring and an absence of hair growth in the affected area.

Abnormalities of the hands and feet are also common in people with Adams-Oliver syndrome. These most often involve the fingers and toes and can include abnormal nails, fingers or toes that are fused together (syndactyly), and abnormally short or missing fingers or toes (brachydactyly or oligodactyly). In some cases, other bones in the hands, feet, or lower limbs are malformed or missing.

Some affected infants have a condition called cutis marmorata telangiectatica congenita. This disorder of the blood vessels causes a reddish or purplish net-like pattern on the skin. In addition, people with Adams-Oliver syndrome can develop high blood pressure in the blood vessels between the heart and the lungs (pulmonary hypertension), which can be life-threatening. Other blood vessel problems and heart defects can occur in affected individuals.

In some cases, people with Adams-Oliver syndrome have neurological problems, such as developmental delay, learning disabilities, or abnormalities in the structure of the brain. https://medlineplus.gov/genetics/condition/adams-oliver-syndrome

Clinical features

From HPO

Short distal phalanx of finger

MedGen UID:: 326590
•Concept ID:: C1839829
•: Finding

Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.

See: Feature record | Search on this feature

Short palm

MedGen UID:: 334684
•Concept ID:: C1843108
•: Finding

Short palm.

See: Feature record | Search on this feature

Short metatarsal

MedGen UID:: 341358
•Concept ID:: C1849020
•: Finding

Diminished length of a metatarsal bone, with resultant proximal displacement of the associated toe.

See: Feature record | Search on this feature

Absent toe

MedGen UID:: 766668
•Concept ID:: C3553754
•: Finding

Aplasia of a toe. That is, absence of all phalanges of a non-hallux digit of the foot and the associated soft tissues.

See: Feature record | Search on this feature

Short 5th toe

MedGen UID:: 866760
•Concept ID:: C4021111
•: Anatomical Abnormality

Underdevelopment (hypoplasia) of the fifth toe.

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2-3 toe syndactyly

MedGen UID:: 1645640
•Concept ID:: C4551570
•: Congenital Abnormality

Syndactyly with fusion of toes two and three.

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Intellectual disability, mild

MedGen UID:: 10044
•Concept ID:: C0026106
•: Mental or Behavioral Dysfunction

Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.

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Delayed gross motor development

MedGen UID:: 332508
•Concept ID:: C1837658
•: Finding

A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.

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Microcephaly

MedGen UID:: 1644158
•Concept ID:: C4551563
•: Finding

Head circumference below 2 standard deviations below the mean for age and gender.

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Short palpebral fissure

MedGen UID:: 98067
•Concept ID:: C0423112
•: Finding

Distance between the medial and lateral canthi is more than 2 SD below the mean for age (objective); or, apparently reduced length of the palpebral fissures.

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Aplasia cutis congenita

MedGen UID:: 79390
•Concept ID:: C0282160
•: Congenital Abnormality

Aplasia cutis congenita (ACC) is defined as congenital localized absence of skin. The skin appears as a thin, transparent membrane through which the underlying structures are visible. The location is usually on the scalp (Evers et al., 1995). Approximately 20 to 30% of cases have underlying osseous involvement (Elliott and Teebi, 1997). Autosomal dominant inheritance is most common, but recessive inheritance has also been reported. Cutaneous aplasia of the scalp vertex also occurs in Johanson-Blizzard syndrome (243800) and Adams-Oliver syndrome (AOS; 100300). A defect in the scalp is sometimes found in cases of trisomy 13 and in about 15% of cases of deletion of the short arm of chromosome 4, the Wolf-Hirschhorn syndrome (WHS; 194190) (Hirschhorn et al., 1965; Fryns et al., 1973). Evers et al. (1995) provided a list of disorders associated with aplasia cutis congenita, classified according to etiology. They also tabulated points of particular significance in history taking and examination of patients with ACC.

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Hypoplastic fifth fingernail

MedGen UID:: 870244
•Concept ID:: C4024682
•: Anatomical Abnormality

A nail of the fifth finger that is diminished in length and width, i.e., underdeveloped nail of little finger.

See: Feature record | Search on this feature

Show all Hide all

Abnormality of head or neck
- Short palpebral fissure
Abnormality of limbs
Abnormality of the integument
- Aplasia cutis congenita
- Hypoplastic fifth fingernail
Abnormality of the musculoskeletal system
- Microcephaly
Abnormality of the nervous system
- Delayed gross motor development
- Intellectual disability, mild

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVAdams-Oliver syndrome
- CROGVAdams-Oliver syndrome 1
- CROGVAdams-Oliver syndrome 2
- CROGVAdams-Oliver syndrome 3
- CROGVAdams-Oliver syndrome 4

Cranial malformation
- Adams-Oliver syndrome
  - Adams-Oliver syndrome 3

Recent clinical studies

Etiology

Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Stanley KJ, Kalbfleisch KJ, Moran OM, Chaturvedi RR, Roifman M, Chen X, Manshaei R, Martin N, McDermott S, McNiven V, Myles-Reid D, Nield LE, Reuter MS, Schwartz MLB, Shannon P, Silver R, Somerville C, Teitelbaum R, Zahavich L, Bassett AS, Kim RH, Mital S, Chitayat D, Jobling RK
Eur J Hum Genet 2024 Jul;32(7):795-803. Epub 2024 May 22 doi: 10.1038/s41431-024-01629-4. PMID: 38778082 Free PMC Article

Ocular Manifestations of Cutis Marmorata Telangiectatica Congenita.

Dedania VS, Moinuddin O, Lagrou LM, Sathrasala S, Cord Medina FM, Del Monte MA, Chang EY, Bohnsack BL, Besirli CG
Ophthalmol Retina 2019 Sep;3(9):791-801. Epub 2019 May 1 doi: 10.1016/j.oret.2019.03.025. PMID: 31147303

Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

Southgate L, Sukalo M, Karountzos ASV, Taylor EJ, Collinson CS, Ruddy D, Snape KM, Dallapiccola B, Tolmie JL, Joss S, Brancati F, Digilio MC, Graul-Neumann LM, Salviati L, Coerdt W, Jacquemin E, Wuyts W, Zenker M, Machado RD, Trembath RC
Circ Cardiovasc Genet 2015 Aug;8(4):572-581. Epub 2015 May 11 doi: 10.1161/CIRCGENETICS.115.001086. PMID: 25963545 Free PMC Article

Syndromes, disorders and maternal risk factors associated with neural tube defects (V).

Chen CP
Taiwan J Obstet Gynecol 2008 Sep;47(3):259-66. doi: 10.1016/S1028-4559(08)60122-9. PMID: 18935987

Adams-Oliver syndrome revisited.

Whitley CB, Gorlin RJ
Am J Med Genet 1991 Sep 1;40(3):319-26. doi: 10.1002/ajmg.1320400315. PMID: 1951437

See all (9)

Diagnosis

Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

Meester JAN, Sukalo M, Schröder KC, Schanze D, Baynam G, Borck G, Bramswig NC, Duman D, Gilbert-Dussardier B, Holder-Espinasse M, Itin P, Johnson DS, Joss S, Koillinen H, McKenzie F, Morton J, Nelle H, Reardon W, Roll C, Salih MA, Savarirayan R, Scurr I, Splitt M, Thompson E, Titheradge H, Travers CP, Van Maldergem L, Whiteford M, Wieczorek D, Vandeweyer G, Trembath R, Van Laer L, Loeys BL, Zenker M, Southgate L, Wuyts W
Hum Mutat 2018 Sep;39(9):1246-1261. Epub 2018 Jul 4 doi: 10.1002/humu.23567. PMID: 29924900 Free PMC Article

Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype.

Hassed S, Li S, Mulvihill J, Aston C, Palmer S
Am J Med Genet A 2017 Mar;173(3):790-800. Epub 2017 Feb 4 doi: 10.1002/ajmg.a.37889. PMID: 28160419

Idiopathic non-cirrhotic portal hypertension: a review.

Schouten JN, Verheij J, Seijo S
Orphanet J Rare Dis 2015 May 30;10:67. doi: 10.1186/s13023-015-0288-8. PMID: 26025214 Free PMC Article

Adams-Oliver syndrome: a case report.

Frantz JA, Lehmkuhl RL, Leitis LH, Uliano VG, Siementcoski GA
Pediatr Dermatol 2015 May-Jun;32(3):383-5. Epub 2014 Dec 29 doi: 10.1111/pde.12423. PMID: 25556654

See all (23)

Therapy

Do children with Adams-Oliver syndrome require endocrine follow-up? New information on the phenotype and management.

Kalina MA, Kalina-Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marszał E, Małecka-Tendera E
Clin Genet 2010 Sep;78(3):227-35. Epub 2010 May 22 doi: 10.1111/j.1399-0004.2010.01470.x. PMID: 20560985

See all (1)

Prognosis

Novel copy number variants and major limb reduction malformation: Report of three cases.

Shamseldin HE, Anazi S, Wakil SM, Faqeih E, El Khashab HY, Salih MA, Al-Qattan MM, Hashem M, Alsedairy H, Alkuraya FS
Am J Med Genet A 2016 May;170A(5):1245-50. Epub 2016 Jan 8 doi: 10.1002/ajmg.a.37550. PMID: 26749485

Severe phenotype in two half-sibs with Adams Oliver syndrome.

Sevilla-Montoya R, Ríos-Flores B, Moreno-Verduzco E, Domínguez-Castro M, Rivera-Pedroza CI, Aguinaga-Ríos DM
Arch Argent Pediatr 2014 Jun;112(3):e108-12. doi: 10.5546/aap.2014.eng.e108. PMID: 24862819

Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase.

Cohen I, Silberstein E, Perez Y, Landau D, Elbedour K, Langer Y, Kadir R, Volodarsky M, Sivan S, Narkis G, Birk OS
Eur J Hum Genet 2014 Mar;22(3):374-8. Epub 2013 Jul 17 doi: 10.1038/ejhg.2013.159. PMID: 23860037 Free PMC Article

Syndromes, disorders and maternal risk factors associated with neural tube defects (V).

Chen CP
Taiwan J Obstet Gynecol 2008 Sep;47(3):259-66. doi: 10.1016/S1028-4559(08)60122-9. PMID: 18935987

Adams-Oliver syndrome revisited.

Whitley CB, Gorlin RJ
Am J Med Genet 1991 Sep 1;40(3):319-26. doi: 10.1002/ajmg.1320400315. PMID: 1951437

See all (8)

Clinical prediction guides

Aplasia cutis congenita in a CDC42-related developmental phenotype.

Schnabel F, Kamphausen SB, Funke R, Kaulfuß S, Wollnik B, Zenker M
Am J Med Genet A 2021 Mar;185(3):850-855. Epub 2020 Dec 7 doi: 10.1002/ajmg.a.62009. PMID: 33283961

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome.

Meester JA, Southgate L, Stittrich AB, Venselaar H, Beekmans SJ, den Hollander N, Bijlsma EK, Helderman-van den Enden A, Verheij JB, Glusman G, Roach JC, Lehman A, Patel MS, de Vries BB, Ruivenkamp C, Itin P, Prescott K, Clarke S, Trembath R, Zenker M, Sukalo M, Van Laer L, Loeys B, Wuyts W
Am J Hum Genet 2015 Sep 3;97(3):475-82. Epub 2015 Aug 20 doi: 10.1016/j.ajhg.2015.07.015. PMID: 26299364 Free PMC Article

Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

Mutations in NOTCH1 cause Adams-Oliver syndrome.

Stittrich AB, Lehman A, Bodian DL, Ashworth J, Zong Z, Li H, Lam P, Khromykh A, Iyer RK, Vockley JG, Baveja R, Silva ES, Dixon J, Leon EL, Solomon BD, Glusman G, Niederhuber JE, Roach JC, Patel MS
Am J Hum Genet 2014 Sep 4;95(3):275-84. Epub 2014 Aug 14 doi: 10.1016/j.ajhg.2014.07.011. PMID: 25132448 Free PMC Article

Clinical and molecular analysis of nine families with Adams-Oliver syndrome.

Verdyck P, Holder-Espinasse M, Hul WV, Wuyts W
Eur J Hum Genet 2003 Jun;11(6):457-63. doi: 10.1038/sj.ejhg.5200980. PMID: 12774039

See all (14)

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Adams-Oliver syndrome 3(AOS3)

Definition

Additional descriptions

Clinical features

Term Hierarchy

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

Related information

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