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Clinical characteristics: 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.
Diagnosis/testing: The diagnosis of AOS can be established in a proband with one of the following:
Clinical findings of ACC of the scalp and TTLD
ACC or TTLD and a first-degree relative with findings consistent with AOS
ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two pathogenic variants in an autosomal recessive AOS-related gene (DOCK6 or EOGT)
Management: Treatment of manifestations:
ACC. Care by a pediatric dermatologist and/or plastic surgeon depending on severity. Goals of non-operative therapy are to prevent infection and promote healing. Large and/or deep lesions with calvarial involvement require acute care and may eventually also require reconstruction by a neurosurgeon.
Limb. Many AOS limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy are used as needed to assist with limb functioning. Rarely, surgical intervention for hand malformations is indicated.
Cardiovascular. Echocardiography annually until age three years for signs of pulmonary hypertension.
Neurologic. Annual pediatric care, including neurologic examination and ongoing assessment of psychomotor development.
Ocular. Annual assessment by pediatric ophthalmologist until age three years for evidence of abnormal retinal vascular development.
Evaluation of relatives at risk: Presymptomatic diagnosis to identify as early as possible those who would benefit from initiation of treatment and/or surveillance for cardiovascular, neurologic, and/or ocular manifestations.
Genetic counseling: ARHGAP31-, DLL4-, NOTCH1-, and RBPJ-related Adams-Oliver syndrome (AOS) are inherited in an autosomal dominant manner. Intrafamilial variability in the extent and severity of cutaneous and limb defects is often striking. The proportion of AOS caused by de novo pathogenic variants is unknown. Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant.
DOCK6- and EOGT-related AOS are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once the AOS-related pathogenic variant(s) have been identified in an affected family member, molecular genetic prenatal testing and preimplantation genetic testing for a pregnancy at increased risk for AOS are possible.
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