Adams-Oliver Syndrome 2
A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-2 (AOS2) is caused by homozygous or compound heterozygous mutation in the DOCK6 gene (614194) on chromosome 19p13.
DescriptionAdams-Oliver syndrome-2 is an autosomal recessive multiple congenital anomaly syndrome characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects, in association with variable involvement of the brain, eyes, and cardiovascular systems (summary by Shaheen et al., 2011).
For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300).
Clinical FeaturesKoiffmann et al. (1988) reported a Brazilian family with Adams-Oliver syndrome suggesting autosomal recessive inheritance. The proband, born of unaffected first cousins, had a congenital scalp defect with hypoplastic fingers and toes. Among 7 sibs, 3 sisters and 2 brothers were normal, whereas 2 brothers born with the same scalp defect died as a consequence of bleeding from this abnormal area.
Orstavik et al. (1995) reported 2 sibs with aplasia cutis congenita, transverse limb anomalies, and congenital vitreoretinal abnormalities: the sister had retinal nonattachment and the brother had a falciform fold in his left eye. The authors concluded that these patients had a more severe phenotype than typical Adams-Oliver syndrome, and suggested that they may represent a new severe variant of the disorder. The healthy parents were unrelated but came from the same small town, and Orstavik et al. (1995) stated that autosomal recessive inheritance seemed most likely.
Klinger and Merlob (1998) reported a brother and sister with AOS. The brother had scalp aplasia cutis congenita and cutis marmorata; his sister had these features associated with terminal lower limb defects, including short upper limbs, short feet, and brachydactyly of toes 2 to 4. Oligohydramnios had been a feature of both pregnancies. The authors also pointed out the report of Kahn and Olmedo (1950) as another example of recessive inheritance.
Tekin et al. (1999) reported a Turkish family with 2 affected sibs and unaffected consanguineous parents as evidence of recessive inheritance in at least some families.
Amor et al. (2000) reported 2 sibs, born of consanguineous parents, with cortical malformations and scalp and limb defects consistent with AOS. Both sibs showed global developmental delay, and brain imaging showed polymicrogyria and dilatation of the cerebral ventricles. One child developed lymphedema of 1 leg. Amor et al. (2000) suggested that the sibs had a rare variant of AOS with autosomal recessive inheritance.
Unay et al. (2001) described a 7-year-old Turkish girl, born of unaffected double first-cousin parents, who presented with seizures and focal alopecia. Her psychomotor development was severely delayed. Dysmorphic features included bitemporal depression, prominent ears, and micrognathia. There was an 8.5-cm diameter area of alopecia in the left frontotemporal region without any underlying bone defect; the remainder of the skin was normal. Her right hand was short, with flexed fingers, and there were only 2 phalanges of digits 2, 3, and 5; on the left, the middle and distal phalanges were absent from all fingers. There was interdigital webbing between toes 2, 3, and 4. Heart was normal by ECG and echocardiography. EEG demonstrated diffuse and slow right hemispheric complex activity due to cerebral cortical dysfunction; CT scan of the brain showed multiple calcifications in the walls of the ventricles. Unay et al. (2001) stated that the triad of microcephaly, epilepsy, and mental retardation is an extremely rare finding in AOS, and that this patient represented the third such reported case.
Temtamy et al. (2007) reported 3 probands with AOS from 3 unrelated consanguineous Egyptian families. The patients had typical skull and limb anomalies with cutis marmorata telangiectatica congenita. The parents were unaffected, and there was a history of similarly affected sibs in 2 of the families. Additional rare manifestations were observed, including microcephaly, psychomotor retardation, epilepsy, eye anomalies, and atrophic skin lesions. MRI of the brain in 1 patient revealed retrocerebellar cyst and mild asymmetric cerebellar hypoplasia, features not previously reported in AOS. Temtamy et al. (2007) stated that their findings provided further evidence of clinical and genetic heterogeneity and supported the presence of an autosomal recessive variant of Adams-Oliver syndrome.
Prothero et al. (2007) reported a male infant, born of consanguineous Afghan parents, with microcephaly, cutis aplasia of the scalp, a wide anterior fontanel, hypoplastic distal phalanges of all 4 limbs, and hypoplastic nails, most marked in his hands and left foot. There were some mild facial dysmorphic features, including posteriorly rotated ears, deep-set eyes, and micrognathia. Ophthalmic examination showed bilateral falciform retinal folds involving the macula. Brain MRI showed periventricular calcifications, slight ventricular dilation, and hypoplasia of the corpus callosum. At 1 year, he had severe developmental delay with truncal hypotonia and increased tone in all 4 limbs.
McGoey and Lacassie (2008) reported 2 sisters with Adams-Oliver syndrome who had central nervous system abnormalities. The proband was born with rudimentary fingers, hypoplastic nails, and near total adactyly of 1 foot and syndactyly of the other. She also had 2 hair whorls, micrognathia, high-pitched cry, sacrococcygeal dimple, cutis marmorata, and microcephaly. She developed seizures at age 7 months, at which time MRI showed near total agenesis of the corpus callosum and periventricular gliosis with calcifications. Her older sister was born with terminal transverse limb defects, including bilateral shortening of the radioulnar bones with hypoplastic digits at the elbows and near total adactyly of the feet. Facial features included hypertelorism, epicanthal folds, blue sclerae, and micrognathia. She also had seizures, developmental delay, microcephaly, and periventricular calcifications. McGoey and Lacassie (2008) reviewed previous reports of autosomal recessive inheritance of Adams-Oliver syndrome, stating that 12 patients from 9 kindreds had been reported. The authors postulated that central nervous system abnormalities may be more common in the recessive form compared to the classic autosomal dominant form.
Balasubramanian and Collins (2009) reported 2 sibs with probable AOS. They were born to nonconsanguineous unaffected parents and had 2 healthy older sibs, suggesting autosomal recessive inheritance. The younger girl was more severely affected than her older brother, and the diagnosis of AOS in the 2 affected sibs only became apparent after she was born. The sister was born with microcephaly, scalp and abdominal wall defects, abnormally small fingers and toes, widely spaced nipples, and brain MRI abnormalities, including thin corpus callosum and periventricular leukomalacia. The brother showed a milder presentation with intrauterine growth retardation, microcephaly, cardiac defects, mild distal limb anomalies, and periventricular calcification. He was reported to have mild developmental delay at age 6 months.
Shaheen et al. (2011) described 2 probands with AOS from 2 unrelated consanguineous Arab families. One patient was an 11-month-old girl with severe and global developmental delay and recurrent seizures, who had 4 normal sibs and 1 cousin who was said to be similarly affected. In addition to a large area of cutis aplasia of the scalp and absence of distal phalanges and nails of the hands and feet, examination revealed microcephaly, optic atrophy, and axial hypotonia with appendicular hypertonia. Echocardiography was normal. Brain CT showed hydrocephalus with dilation of the lateral ventricles and multiple small periventricular and subependymal calcifications. The other patient was a 3.5-year-old girl with terminal reduction defects of the hands and feet, cutis aplasia of the scalp, and speech delay, in whom echocardiography, EEG, and eye examination were normal. Both sets of parents were healthy.
Sukalo et al. (2015) studied 12 patients from 10 families with molecularly proven AOS2. Limb defects ranged from minimal hypoplasia of terminal phalanges to severe transverse reduction defects. In addition to aplasia cutis congenita of the scalp, 4 patients had areas of ACC on the abdomen. All patients from whom sufficient data could be obtained were reported to have developmental delay or mental retardation, ranging from mild to severe. A broad range of additional neurologic abnormalities were reported in most cases, including cerebral palsy, spasticity, contractures, and epilepsy. Only 1 of the 7 patients who were more than 4 years old had achieved the ability to walk without support. Brain MRI or CT scan was performed in 7 patients, and was abnormal in all cases. The most frequent changes included ventriculomegaly, periventricular leukomalacia and/or calcifications, and hypoplasia or atrophy of the corpus callosum. Head circumference measurements were available for 8 patients and were in the microcephalic range for all. Ocular anomalies included microphthalmia and retinal detachment, and visual impairment was present in all patients for whom clinical information was available. In contrast, cardiac anomalies were observed in only 3 cases. Sukalo et al. (2015) noted that AOS2 appears to be strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, and suggested that it represents a variant of AOS with a particularly poor prognosis.
InheritanceThe transmission pattern of Adams-Oliver syndrome in the families reported by Shaheen et al. (2011) was consistent with autosomal recessive inheritance.
Molecular GeneticsBy combining autozygome data with next-generation sequencing in an 11-month-old Arab girl with autosomal recessive AOS, Shaheen et al. (2011) identified a homozygous 4-bp deletion in the DOCK6 gene (614194.0001), which was found in heterozygosity in her unaffected parents. Analysis of DOCK6 in a 3.5-year-old Arab girl with AOS revealed a homozygous 1-bp duplication (614194.0002) that segregated with disease in her family.
In affected individuals from 2 consanguineous Arab families with AOS who shared a region of homozygosity overlapping the DOCK6 gene, Shaheen et al. (2013) identified homozygous mutations in DOCK6 (614914.0003 and 614914.0004, respectively).
In 14 affected individuals from 12 unrelated families with AOS, Stittrich et al. (2014) screened for variants in AOS-associated genes and identified 1 individual who was compound heterozygous for mutations in the DOCK6 gene.
Sukalo et al. (2015) analyzed the DOCK6 gene in 88 AOS patients from 78 unrelated families and identified probands from 10 families with biallelic mutations, including compound heterozygosity for a missense mutation (V263D; 614194.0005) and a splice site mutation (614194.0006) in the 2 sibs originally reported by Orstavik et al. (1995), and homozygosity for a missense mutation (E1052K; 614194.0007) in the Afghan male infant previously reported by Prothero et al. (2007). The overall proportion of DOCK6-related AOS across the complete cohort was 13%, with a frequency of 29% among families suggestive of autosomal recessive inheritance and 2% among sporadic cases. Sukalo et al. (2015) stated that AOS2 is strongly associated with cerebral and ocular anomalies in addition to aplasia cutis congenita and transverse terminal limb defects, and suggested that DOCK6 should be the primary candidate gene for investigation in patients with such a constellation of features.