Paula and Bobby
Parents of Lillie
Adams-Oliver syndrome 1; AOS1
What is Adams-Oliver syndrome 1; AOS1?
Adams-Oliver syndrome 1; AOS1 is a rare disease. It is also known as Absence Defect Of Limbs, Scalp, And Skull Aos Aplasia Cutis Congenita With Terminal Transverse Limb Defects Congenital Scalp Defects With Distal Limb Reduction Anomalies.
The term ectrodactyly is sometimes used to describe a split hand or foot, but more correctly to refer to a terminal transverse defect of the limb. The latter can occur with scalp defects as an autosomal dominant condition. Small defects of the skull bones, underlying the scalp defect, are also sometimes seen. Occasionally the scalp defects can be extensive, affecting the cranial vault and underlying vessels and leading to life-threatening haemorrhage. A case with focal scalp hair loss with normal underlying skin was reported by Girish et al., (2014). Fryns et al., (1996) reported a case with right spastic hemiplegia with a left porencephalic cyst, probably secondary to hypoplasia of the left medial cerebral artery. Neuronal migration defects might also occur (Brancati et al., 2008). Frank and Frosch (1993) noted the association with cutis marmorata telangiectatica congenita. Chitayat et al., (1992) reported a case with acrania. Savarirayan et al., (1999) reported a case with unilateral severe cortical dysplasia of the central, occipital and anterior regions of the right cerebral hemisphere. An ischemic retinopathy has also been reported (Peralta-Calvo et al., 2012).
The limb defects usually consist of terminal reductions of the fingers and toes. Although most affected individuals have relatively minor limb defects, the condition is very variable and occasionally severe limb defects can be present. For example, in the original case report by Adams and Oliver (1945) the proband had bilateral below the knee hemimelia and several other family members were severely affected. A case reported by Heras Mulero et al., (2007) had normal limbs, but had coarctation of the aorta. A broad fingertip with underlying bifid distal phalanx was noted by Baskar et al., (2009).
It should be noted that the limb defects in this condition can look like amniotic band deformities (Savarirayan et al., 1999 and Keymolen et al., 1999). Sybert (1985) reported cases with this combination (family 7 and family 8). The proband in family 8 had a scalp defect and limb defects consistent with amniotic bands. Her 6-year-old sister had two scalp defects with normal extremities and the parents were normal.
Congenital heart defects may be part of the condition. Ishikiriyama et al., (1992) presented a case and reviewed seven from the literature. Four cases had a VSD and three had tetralogy of Fallot. Zapata et al., (1995) reported two cases, one with subaortic stenosis and the other with a parachute mitral valve. Lin et al., (1998) reported four cases with heart defects. Swartz et al., (1999) reported a case with a double outlet right ventricle, portal hypertension, and pulmonary hypertension. They suggested that the other lesions in Adams-Oliver syndrome are secondary to an early embryonic vascular abnormality. Maniscalco et al., (2005), reported a man and his son with Adams-Oliver. Both had pulmonary arterio-venous malformations. A fetus was reported (Wloch et al., 2006) with premature closure of the ductus. Pereira da Silva et al., (2000) reported two cases with distal ischemic lesions and necrosis of the digits, also suggesting a vascular aetiology. Another case with pulmonary hypertension was reported by Piazza et al., (2004). Girard et al., (2005) found two unrelated cases with Adams-Oliver and hepatoportal sclerosis, and also suggested a vasculopathy or predisposition to thrombosis as cause. They mentioned the resemblance to macrocephaly - cutis marmorata syndrome, that may have a similar aetiology. Pouessel et al., (2006) reported an additional case with hepatoportal sclerosis and Dadzie et al., (2007), a case with cutis marmorata telangiectasia congenita and multiple areas of stenosis in the pulmonary artery.
Farrell et al., (1993) reported a case with juvenile chronic myelogenous leukaemia and a chylothorax. Romani et al., (1998) reported a case with intracranial periventricular calcification with ventricular dilatation. Calcification and a hypoplastic corpus callosum were also found in the patient reported by Piazza et al., (2004).
Verdyck et al., (2003) reported nine further families and excluded the ALX4 and MSX2 genes as candidates by linkage and mutation analysis. Patel et al., (2004) reported a case with cutis marmorata, intracranial bleeding and pulmonary hypertension, who was found at PM to have defective vascular smooth muscle cell/pericyte coverage of the vasculature
The condition has now been mapped to 3q13 and mutations have been found in ARHGAP31 (Southgate et al., 2011). Mutations have also been found in RBP2 (Hassed et al., 2012)., a transcriptional region regulator for the NOTCH pathway. Mutations in NOTCH1 are also causative as are mutations in DLL4 (Meester et al., 2015).
Adams-Oliver syndrome is inherited in an autosomal dominant or an autosomal recessive manner. Autosomal recessive forms are more severe. It is characterized by aplasia cutis congenita, terminal transverse limb defects and additional congenital abnormalities.
Families without DOCK6 mutations were evaluated by Shaheen et al., (2013). They mapped to 3p14.1 and mutations were found in EOGT which encodes O-GlcNAc. Cohen et al., (2014) described further families homozygous for EOGT mutations.
Hassed et al. (2017) reviewed 385 previously reported patients (139 non-familial and 246 familial probands and family members) and 13 unreported individuals with Adams-Oliver syndrome. Aplasia cutis congenita was present in the scalp in 99% of case. Other features were small nails (51%), cutaneous syndactyly, bony syndactyly, or both (29%), brain anomalies (35%) and microcephaly (7%). Most frequent central nervous system abnormalities included calvarial defect without brain anomaly (25%), calvarial defect with brain anomaly (11%), microcephaly with other anomalies (6%), calcifications secondary to vascular sequelae (5%), enlarged ventricles (5%), isolated microcephaly (4%), thin or absent corpus callosum (4%). Most frequent heart and vascular defects were cutis marmorata telangiectasia congenita (19%), no anomalies (10%), prominent vessels (8%), bicuspid or parachute aortic valve (6%), ventricular septal defect (6%), tortuous vessels (5%), and atrial septal defect (5%). Liver abnormalities were present in 11% of probands. Cutis marmorata telangiectasia congenita was found in 19% of the probands and other vascular anomalies were seen in 14%. Hemorrhage was listed as the cause of death for 5/25 deaths reported. Affected individuals in nonfamilial cases were reported to have hepatoportal sclerosis with portal hypertension and oesophageal varices.
* This information is courtesy of the L M D.
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What gene changes cause Adams-Oliver syndrome 1; AOS1?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 100300 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
NOTCH1 - 9q34.3
EOGT - 3p14.1
ARHGAP31 - 3q13.32-q13.33
DLL4 - 15q15.1
RBPJ - 4p15.2
DOCK6 - 19p13.2
What are the main symptoms of Adams-Oliver syndrome 1; AOS1?
The typical symptoms of the syndrome are:
Supernumerary nipple, Phenotypic variability, Pulmonary artery stenosis, Ventricular septal defect, Tetralogy of Fallot, Calvarial skull defect, Pulmonic stenosis, Microcephaly, Small nail, Pulmonary arterial hypertension, Talipes equinovarus, Autosomal dominant inheritance, Polymicrogyria, Seizure, Pachygyria, Periventricular leukomalacia, Toe syndactyly, Autosomal recessive inheritance, Global developmental delay, Abnormality of the genitourinary system, Hypoplasia of the corpus callosum, Muscular hypotonia, Intellectual disability, Microphthalmia, Abnormality of the rib cage, Atrial septal defect, Aplasia cutis congenita over posterior parietal area, Aplasia cutis congenita on trunk or limbs, Alopecia, Cutis marmorata, Cortical dysplasia, Cleft upper lip, Cleft palate, Esotropia, Encephalocele, Brachydactyly, Ventriculomegaly
How does someone get tested for Adams-Oliver syndrome 1; AOS1?
The initial testing for Adams-Oliver syndrome 1; AOS1 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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