Adams-Oliver syndrome (ORPHA:974)
A rare multiple congenital anomalies/dysmorphic syndrome characterized by the combination of congenital distal limb reduction and scalp defects, often accompanied by skull ossification defects.
Epidemiology
The prevalence is unknown.
Clinical description
The severity of the disorder varies greatly among affected individuals. Aplasia cutis congenita, transverse limb defects and cutis marmorata telangiectasia congenita are characteristic of this condition. The affected patients typically have malformations of the hands and/or feet that range from hypoplastic phalanges to absent fingers and/or toes. AOS may be associated with a variety of physical anomalies including congenital cataract, strabismus and microphthalmia, congenital heart malformations (including tetralogy of Fallot and pulmonary atresia), and hepatoportal sclerosis. Hydrocephalus is the principal cerebral feature and epilepsy may be associated. Extensive lethal anomalies are possible but very rare. Most frequent signs are vertex aplasia, distal limb reduction, intrauterine growth retardation, and neurodevelopmental delay. The penetrance of the disease seems decreased in AOS of autosomal recessive transmission, with intrafamilial variability, and rare patients may present without aplasia cutis congenita and/or limb reduction.
Etiology
The etiopathogenesis remains unclear, but 2 pathways are implied: NOTCH pathway and RAC1/CDC42 pathway. To date, 6 genes have been described in Adams-Oliver syndrome: ARHGAP31 (autosomal dominant; AD), DLL4 (AD), RBPJ (AD), NOTCH1 (AD), EOGT (autosomal recessive; AR), and DOCK6 (AR). An important inter- and intra-familial variability in expression is described, and an incomplete penetrance. Surprisingly, the penetrance seems to be decreased for recessive transmission. There is no obvious phenotypic difference between those who have missense variations and those who have frameshift or stop-gain variations.
Diagnostic methods
Diagnosis is suspected on clinical presentation, with the association of aplasia cutis congenita and distal limb reduction. It can be confirmed by genetic testing (genes panel, exome or genome sequencing).
Differential diagnosis
The principal differential diagnosis is the recently described FOSL2-related neurodevelopmental disorder with scalp and enamel defects (also presenting sometimes with distal limb reduction). Other genetic differential diagnoses present with scalp defects or distal limb reduction associated syndrome such as Poland sequence, SCALP syndrome, or aplasia cutis congenita (non-exhaustive list). This kind of distal limb defects can also be due to constriction rings of amniotic membranes.
Antenatal diagnosis
Antenatal diagnosis can be performed when ultrasounds reveal distal limb anomalies and/or vertex defects. When a pathogenic variant is identified in a family, antenatal diagnosis is possible depending on the severity of the malformations in the family. Antenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Adams Oliver syndrome variant.
Genetic counseling
Occurrence can be familial or sporadic. Transmission depends on the affected genes; most cases are transmitted as an autosomal dominant trait (ARHGAP31, DLL4, RBPJ, NOTCH1), but some show autosomal recessive transmission (EOGT and DOCK6). Genetic counseling should be offered to at-risk couples: when the transmission is autosomal recessive, there is a 25% risk of having an affected child at each pregnancy, whereas when the transmission is autosomal dominant, there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Limb and scalp defects require orthopedic treatment. Management is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, cardiologists, as well as social support networks.
Prognosis
Life expectancy mostly depends on the severity of the vertex aplasia and of the heart malformation(s). Functionality in everyday life depends on the type and severity of upper-limb anomalies, cerebral malformations, heart and kidney defects, and eyes anomalies.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Dr Perrine BRUNELLE | ITHACA*


                                * European Reference Network