Adams-Oliver Syndrome

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.

Surveillance:

• 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.

Suggestive Findings

Adams-Oliver syndrome (AOS) should be suspected in individuals with the following clinical findings:

• Aplasia cutis congenita (ACC). ACC of the scalp (most often over the posterior sagittal suture) is the classic finding; it may range from the most severe finding of total absence of an area of skull and dura to the mildest finding: hairless patches of varying size at the vertex of the scalp detected on a focused examination of the scalp.
  Of note, when a scalp lesion is not obviously cutis aplasia (e.g., a simple hairless lesion may appear similar to nevus psiloliparus or nevus sebaceous), a skin biopsy can confirm the characteristic features of absent epidermis, dermal atrophy, and lack of adnexal structures and elastic fibers. Generally, a skin biopsy is not necessary because a nevus sebaceous has a yellowish waxy appearance versus the eroded or scarred appearance of ACC.
• Terminal transverse limb defects (TTLD) spectrum, which can include small distal phalanges, short distal phalanges, brachysyndactyly, or ectrodactyly. Note: Many unaffected infants have small toenails at birth.
• Cardiovascular defects with ACC or TTLD [Digilio et al 2008]
  • Almost any type of heart malformation can occur in AOS.
  • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi.
  • Widespread cutis marmorata telangiectatica congenita is common (19%).
• Neurologic findings with ACC or TTLD. Although most individuals with AOS do not have neurologic involvement, frequent neurologic findings in a subset of people include intellectual disability, seizures, or cerebral palsy. Of note, intellectual disability is rare in the absence of a structural brain anomaly or microcephaly.

Establishing the Diagnosis

The diagnosis of Adams-Oliver syndrome (AOS) is established in a proband with one of the following:

• The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD)
• Either ACC or TTLD and a first-degree relative with findings consistent with AOS
• Either ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene or biallelic pathogenic variants in an autosomal recessive AOS-related gene identified on molecular genetic testing (Table 1)

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered if mutation of a particular gene accounts for a significant proportion of Adams-Oliver syndrome (AOS) in which the mode of inheritance is known (Table 1) and/or certain clinical findings (such as neurologic involvement) are present.

Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, it is unknown at present what proportion of individuals with AOS harbor intragenic deletions or duplications that cannot be detected by sequence analysis.

• For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: NOTCH1 and DLL4 are the most frequently mutated AOS-related genes.
• For autosomal recessive AOS with neurologic and ocular abnormalities: DOCK6 analysis may be particularly indicated.

A multigene panel that includes ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, RBPJ, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, and RBPJ) fails to confirm a diagnosis in an individual with features of AOS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). Additional major features frequently include cardiovascular malformations/dysfunction and less frequently, renal and brain anomalies (Table 2) [Snape et al 2009].

The severity of malformations ranges from subtle to disabling or life threatening; variability among family members is common. Although rare, severe morbidity and mortality in AOS usually results from hemorrhage or infection involving large and deep calvarial lesions, or from cardiovascular anomalies including severe heart malformations. At least five children with AOS have died from refractory pulmonary hypertension (~1% risk), all in the first three years of life.

Possible Phenotype Correlations by Gene

While subtypes of AOS have not been established, emerging data suggest:

• High risk for severe brain involvement in DOCK6-AOS (autosomal recessive inheritance) and less risk in ARHGAP31-AOS (autosomal dominant inheritance).
• Increased risk for cardiac defects in NOTCH1-, DOCK6-, DLL4-, and EOGT-AOS and lower risk in RBPJ- and ARHGAP31-AOS.

ARHGAP31. The risk for cerebral involvement with this autosomal dominant form of AOS appears to be less than for the autosomal recessive forms, as to date neurologic abnormalities have not been reported in individuals with ARHGAP31-AOS.

DLL4. A significant minority of individuals have cardiovascular anomalies.

DOCK6. Approximately 15 families/probands with DOCK6-AOS have been reported. A cohort-based study yielded likely pathogenic DOCK6 variants in 29% (9/31) of families with suspected autosomal-recessive inheritance versus 2% (1/47) of simplex cases [Sukalo et al 2015]. To date, severe intellectual and neurologic impairments appear to be consistent findings in DOCK6-AOS, with findings in keeping with disturbed intracranial vasculogenesis. Ocular malformations and retinal issues are also seen more common in this subgroup; cardiac malformations have been reported as well.

EOGT. Periventricular calcifications and cardiovascular anomalies occurred in a significant minority [Shaheen et al 2013].

NOTCH1. NOTCH1-AOS appears to show a particularly high rate of cardiac malformations and vasculopathy, occurring in at least half of affected individuals [Stittrich et al 2014, Southgate et al 2015]. Thrombotic occlusive or sclerotic portal venopathy leading to portal hypertension has been seen in several individuals, more commonly in simplex cases. Two children with NOTCH1-AOS have had pulmonary hypertension, which was mild in one [Southgate et al 2015] and transient in the other [Stittrich et al 2014]. At least one individual had neurologic deficits (spastic diplegia and intellectual disability) in the context of intracranial vascular lesions.

RBPJ. Intellectual impairment was a variable feature in both families reported with RPBJ-AOS [Hassed et al 2012].

Genotype-Phenotype Correlations

For the genes known to be associated with Adams-Oliver syndrome, no genotype-phenotype correlations (either with a class of pathogenic variants or with any specific pathogenic variants) have been identified.

Penetrance

Familial autosomal dominant AOS typically shows decreased penetrance.

• NOTCH1 and DLL4. Incomplete penetrance was observed in at least 2/9 families with a NOTCH1 pathogenic variant and 3/16 families with a DLL4 pathogenic variant (and likely more) [Stittrich et al 2014, Meester et al 2015, Southgate et al 2015].
• RBPJ. Incomplete penetrance has not been reported to date.
• ARHGAP31. In one large pedigree with limb anomalies, but no cutis aplasia, 3/16 (19%) heterozygotes had no clinical manifestations of AOS [Isrie et al 2014]. In two other large pedigrees, only one individual was noted to have no clinical manifestations of AOS [Southgate et al 2011].

Nomenclature

A sporadic co-occurrence of ACC and TTLD was first reported by Pincherle [1938], seven years before the description of a large family with several affected family members [Adams & Oliver 1945].

Prevalence

An estimate of the incidence for AOS is 0.44 per 100,000 live births [Martínez-Frías et al 1996].

The authors' experience in a tertiary pediatric care center supports a somewhat higher incidence, and further recognition of milder phenotypes within the spectrum of AOS may yet reveal a significantly higher incidence.

Syndromic Aplasia Cutis Congenita (ACC)

Scalp-ear-nipple (SEN) syndrome (Finlay-Marks syndrome; OMIM 181270). Clinical findings include the following:

• Variable combinations of ACC of the scalp (usually in the vertex or occipital region), hypothelia / athelia, mammary hypoplasia, ear anomalies (either cupped, overfolded, or hypoplastic)
• Variable digital anomalies including distal hypoplasia, syndactyly and camptodactyly
• Occasional hypodontia, renal hypoplasia / malformations or ocular anomalies (colobomata or cataracts)
• Normal intellectual development; however, affected sibs in one family presented with severe hypotonia and developmental delay, and a severe autosomal recessive form of the condition was suspected [Al-Gazali et al 2007].

SEN syndrome is caused by mutation of KCTD1 and is inherited in an autosomal dominant manner. (Reported KCTD1 pathogenic variants were predicted to disrupt the domain responsible for repressing TFAP2A transcriptional activity. TFAP2A pathogenic variants are the cause of branchiooculofacial syndrome which can often feature scarred branchial and auricular skin lesions in keeping with healed cutis aplasia.)

Focal dermal hypoplasia (Goltz syndrome)

• Multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face
• Can feature both cutis aplasia and limb anomalies (syndactyly, polydactyly, camptodactyly or oligodactyly).
• A distinguishing feature from AOS is that the dermal hypoplasia usually follows lines of Blaschko.
• Other distinguishing features include ectodermal dysplasia, subepidermal deposits of subcutaneous fat, metaphyseal striations, and papillomas of the skin and mucous membranes.

Focal dermal hypoplasia is inherited in an X-linked manner. Females (90% of affected individuals) are heterozygous or mosaic for a PORCN pathogenic variant. Live-born affected males (10% of affected individuals) are mosaic for a PORCN pathogenic variant.

Dominant dystrophic epidermolysis bullosa (DDEB)

• Typically, ACC lesions are restricted to the limbs and the clinical diagnosis is clear from persistent skin fragility and blistering postnatally.
• Limb anomalies are generally limited to absence of the nails.
• DDEB is caused by mutation of COL7A1.

Other causes of syndromic aplasia cutis congenita (ACC)

• Chromosome disorders
  • Trisomy 13 (Patau syndrome)
  • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM 194190)
• Setleis syndrome (focal facial dermal dysplasia 3; OMIM 227260), with bitemporal or preauricular skin lesions resembling ACC
• Johanson-Blizzard syndrome (see Pancreatitis Overview)
• Oculocerebrocutaneous (Delleman) syndrome (OMIM 164180)
• Kabuki syndrome
• Limb body wall complex
• Knobloch syndrome (OMIM 267750), with high myopia, neuronal elements in scalp defects, occipital encephalocele
• Various ectodermal dysplasias

Isolated aplasia cutis congenita (ACC)

• Estimated to occur in one in 3,000 live births, most often as an isolated, sporadic malformation [Marneros 2015].
• Familial recurrence is rarely observed, and can be caused by a heterozygous pathogenic variant in BMS1 (OMIM 107600), a ribosomal GTPase that recruits Rcl1 to preribosomes and promotes ribosomal subunit maturation [Karbstein & Doudna 2006].
• Hypoproliferation and/or impaired differentiation at a location of rapid growth (the cranium) have been hypothesized as part of the pathogenesis for this condition [Marneros 2015].

Non-genetic causes of aplasia cutis congenita (ACC)

• Birth trauma (e.g., scalp electrode avulsion)
• Amniotic bands
• Intrauterine vascular disruption (e.g., secondary to embolism from co-twin loss)
• Teratogens (misoprostol, cocaine, methotrexate, angiotensin-converting enzyme inhibitors, methimazole, benzodiazepines, valproic acid) [Brzezinski et al 2015].

Terminal Transverse Limb Defects (TTLD)

Amniotic band sequence (OMIM 217100). Considering that the concurrence of transverse distal limb anomalies with cutis aplasia is diagnostic of AOS, there is not an immediate differential diagnosis for this particular combination of features with the notable exception of amniotic band sequence, which can present as a complete phenocopy, particularly if bands have not been observed on prenatal ultrasonography or at delivery. Since constriction rings of the limbs or toes have been described with AOS, this feature does not fully distinguish these two conditions. It is somewhat unusual for amniotic bands to cause focal scalp defects; in contrast, defects at the vertex of the scalp are most consistent with AOS (but may occur elsewhere). Some clinicians do not diagnose amniotic band sequence unless band tissue is physically present or is seen on prenatal ultrasound examination, or the amnion is torn or knotted on placental analysis. In the absence of physical evidence for amnion disruption, constriction rings may be interpreted as evidence of vascular disruption.

Congenital dyserythropoietic anemia type I

• Toes and fingers show limb reductions with absent or hypoplastic nails, often involving partial syndactyly.
• Duplicated metacarpals or metatarsals may be seen.
• Other features are mild to moderate macrocytic anemia and evidence of ineffective erythropoiesis on bone marrow aspirates.
• Jaundice, early onset gallstone formation, and splenomegaly may also be seen.
• CBC with blood smear should be performed in patients with TTLD to assess for the macrocytic anemia of congenital dyserythropoietic anemia.
• Congenital dyserythropoietic anemia type I is caused by mutation of CDAN1 or CDIN1 (C15ORF41) and is inherited in an autosomal recessive manner.

Poland syndrome (OMIM 173800). Key features are unilateral hypoplasia or aplasia of part or all of the pectoralis major, ipsilateral axillary hypohidrosis, and ipsilateral upper limb reduction defects, often with syndactyly.

Hypoglossia-hypodactylia anomaly (Hanhart "syndrome"; OMIM 103300). Key features are small or absent mandibular structures (variably involving mandible, lower incisors, and tongue) and symmetric or asymmetric limb defects.

Non-genetic causes of TTLD

• Teratogens (e.g., phenytoin, misoprostol, and ergotamine) [Holmes 2002].
• Vascular disruption of any cause, including thrombosis, which may be primary due to fetal thrombophilia or may be secondary to other causes such as embolism from co-twin loss
• Chorionic villus sampling (CVS), particularly when performed prior to ten weeks' gestation

Other

Use of exome sequencing. The following are examples in which the use of exome sequencing (in clinical practice) facilitated the diagnosis of Adams-Oliver syndrome when other syndromes initially had been suspected and vice versa:

One individual with retinopathy of prematurity, small toes, VSD, but no cutis aplasia, was diagnosed initially with Coffin-Siris syndrome. Exome sequencing, however, identified biallelic DOCK6