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Diagnosis and Treatment

Clinical Features

Aplasia cutis congenita (ACC), which is the congenital localized absence of skin and lesions of skull, and terminal transverse limb defects (TTLD) are the key features of AOS [1]. However, these traits are not unique to AOS. For example, ACC can present in Johanson-Blizzard syndrome. A scalp defect can sometimes also be observed in trisomy 13, deletion of the short arm of chromosome 4, and the Wolf-Hirschhorn syndrome [2].

Scalp Defects
Picture showing scar of ACC
The most common site of ACC is the vertex, which is the upper surface of the head. The scalp defect is often associated with an underlying skull defect, and the degrees of severity vary with the head structures involved. It is noteworthy that a bony defect can present without scalp defect, and a skull X-ray is suggested to find out the extent of the anomaly [2].
In most cases with scalp defect but not brain and cranial defect, patients can be managed conservatively. Nevertheless, hemorrhage or infection can lead to severe manifestations with a mortality rate of between 20% and 55% [2,3].

Limb Defects
Pictures showing terminal transverse limb defects, including the absence of toenail.
Asymmetrical limb defects on both sides are commonly observed. The severity ranges from minor nail abnormalities to absence of long bone, including hypoplastic nails, cutaneous syndactyly, bony syndactyly, transverse reduction defects, ectrodactyly, polydactyly, and brachydactyly [2].

Other Features…

Some other features are also observed in AOS cases. Since AOS is a rare disease and its spectrum is very broad, the features listed below do not form a complete list of AOS related conditions. Also, keep in mind that these features are NOT diagnostic and can relate to other problems.

Cutis marmorata telangiectatica congenita (CMTC)
CMTC is a rare condition with complex blood vessel malformation, showing a net-like, segmental pattern. The pathogenesis of CMTC is believed to be a vascular defect. CMTC presents in 12-21% AOS patients [4].
Pictures showing CMTC

YouTube explaining CMTC
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Congenital cardiac malformations
The structural cardiac abnormalities in AOS vary widely, but there is a common association between cardiac defects and vascular defects in AOS, providing evidence to the vascular pathogenic hypothesis. Congenital cardiac defect presents in 13-20% AOS patients. The potential pathology will be discussed in the Vasculopathy section [2,4].

Vascular features
Both structural, such as incomplete development or absence of blood vessels, and functional abnormalities, Pulmonary Hypertension (PH) for example, are found in past studies [2]. Vascular abnormalities are associated to many other features observed in AOS individuals.

Neurological features
Neurological involvement is more commonly reported in autosomal recessive individuals than in autosomal dominant individuals with AOS. In autosomal dominant individuals, neurological problems tend to occur with other vascular abnormalities. In autosomal recessive individuals, a more server neurological condition, including microcephaly, mental retardation, and intracranial abnormalities, can be observed [2].

Ocular features
Some AOS patients also have ophthalmological findings. Some examples are cataracts, esotropia , microphthalmia.  Clinical examinations can reveal additional features that are harder to observe: optic disk drusen, retinal folds, bilateral retinal detachment, unususal choroidal architecture, and rod dystrophy [2,5].

Diagnostic Criteria

The highly variable clinical features and the lack of diagnostic test make the identification of AOS difficult, particularly in individuals with de novo gene changes that are absent in their families.  Therefore, a 2009 study [2] suggests that major and minor criteria should be used to achieve a diagnosis of AOS.

Major features Minor features
Terminal transverse limb defects (TTLD) Cutis marmorata telangiectatica congenital (CMTC)
Aplasia cutis congenita (ACC) Congenital cardiac defect
Family history of AOS Vascular anomaly

If two major features are present, then AOS is usually diagnosed.  If one major feature and one minor feature are present, then AOS is strongly suggested.

Pathology

The cause of AOS is largely unknown. However, more and more evidence supports the vascular pathology hypothesis. The blood vessel anomalies can at least partly explain the scalp and skull defects and limb defects. Moreover, some other less consistent features such as CMTC, heart defect, neurological abnormalities, and even ocular abnormalities, are closely associated with vascular abnormalities. You can read more about this hypothesis under the Vasculopathy section.

Researchers try to find the genes responsible for AOS, but many candidate genes fail the test. Recently, mutations in ARHGAP31 and DOCK6 genes are identified in AOS patients. ARHAGP31 underlies autosomal dominant AOS while DOCK6 underlies autosomal recessive AOS. However, these identified mutations cannot explain all the clinical features observed in different AOS patients. By further examining related genes in different patients other disorder-causative genes can be identified in the future. A brief discussion of these two genes can be found in the Disruption of Actin Cytoskeleton Organization and the Genes section.

Therapy

A multidisciplinary approach to the organs affected by different symptoms is suggested for AOS patients [3].

Aplasia cutis congenita Management

Aplasia cutis congenita (also known as cutis aplasia) is one of the main characteristics of AOS, and around 75% AOS individuals are affected. The degrees of severity can range from absence of a small region of skin to exposure of dura mater and deeper meninges [3].

There is agreement on the management of small lesions, and conservative management is recommended [3].

When the defects are extensive, a management dilemma arises. Mortality rates associated with both conservative treatment and with surgical repair are around 20% [3]. The goal of the treatment is to completely close the defect and to avoid major complications, such as meningitis, hemorrhages, and trauma to the brain. Appropriate management is determined by the size of the defect, the degree of skull defect, additional risk factors (cerebrospinal fluid leakage and uncommon dural blood vessels for example), and the child’s general condition [3,6].

Conservative Treatment

The conservative treatment avoids the potential surgical complications and the failure of skin flap or graft. In addition to perioperative risks, surgical procedure may inhibit the potential of dura to repair bone defect [7].

Treatment regimens include several elements: daily wound care with moist sterile gauze, topical application of the antimicrobial agents and a systemic antibiotic therapy for the first several weeks, treatments that reduce the bacterial load and avoid dehydration of the wound [3]. Since povidone-iodine dressings could lead to wound desiccation, they should be avoided to prevent fatal complication of bleeding [3].

The potential complications during conservative treatment include: meningitis, significant hyponatremia with seizures, and brain herniation. Death caused by massive hemorrhage was also reported [3].

Surgical Treatment

Large lesions can involve skull defect, brain tissue exposure, cerebralspinal fluid leakage, and uncommon dural blood vessel. When the lesions are extensive, early surgical intervention is recommended to prevent meningitis, sinus thrombosis or hemorrhage, and a ~20% mortality rate secondary to infection [3,6].

Treatment regimens include skin and bone grafts, local scalp flaps, or free flaps to close the defect [7]. Due to the size of the defect or the associated abnormality of the adjacent skin, a high risk of partial or total graft failure is involved in addition to surgery-related risk of haemorrhage and perioperative infection [3].

Another concern is the lack of consensus about the size of lesions that are appropriate for surgery. Beekmans and Wiebe advised that sizes >1cm should undergo surgery, while Santos et al. elected conservative treatment and Steinbok elected primary  closure for lesions >2cm. Ross et al. recommended skin grafts for lesions with a diameter of >5cm [3].

 

Different authors have come to the agreement that a combined regimen of conservative and surgical treatment for ACC should be used based on the patient’s condition.

 

Endocrine Therapy Case Report

AOS has a broad spectrum of clinical features, and delayed psychomotor development, short status and other anthropometric abnormalities have been reported. These features may imply the involvement of the endocrine system, which regulates hormone in the body and thus the slow body processes, such as growth, development and metabolism. However, few study looked at the potential role of endocrine mechanism in AOS. A 2010 study by Kalina-Faska et al. is the first report on growth pattern and hormonal assessment in patients with AOS.

Low insulin-like growth factor (IGF-1) level and growth hormone (GH) deficiency were observed in a girl with delayed psychomotor development and significant height deficit. MRI revealed polymicrogyria that was associated with developmental delay. GH therapy provided correction of height and improvement in motor coordination. Up to the publication of this article, no GH-related adverse effect was observed. However, long-term safety and other issues need to be taken into consideration [8].

Reference

1.         Patel MS, Taylor GP, Bharya S, Al-Sanna’a N, Adatia I, Chitayat D, et al. Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams–Oliver syndrome. American Journal of Medical Genetics Part A. 2004 Sep 1;129A(3):294–9.
2.         Snape KMG, Ruddy D, Zenker M, Wuyts W, Whiteford M, Johnson D, et al. The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects. American Journal of Medical Genetics Part A. 2009 Aug 1;149A(8):1860–81.
3.         Khashab ME, Rhee ST, Pierce SD, Khashab YE, Nejat F, Fried A. Management of large scalp and skull defects in a severe case of Adams-Oliver syndrome. J Neurosurg Pediatr. 2009 Dec;4(6):523–7.
4.         Jaeggi E, Kind C, Morger R. Congenital scalp and skull defects with terminal transverse limb anomalies (Adams-Oliver syndrome): report of three additional cases. Eur. J. Pediatr. 1990 May;149(8):565–6.
5.         Piazza AJ, Blackston D, Sola A. A case of Adams–Oliver syndrome with associated brain and pulmonary involvement: Further evidence of vascular pathology? American Journal of Medical Genetics Part A. 2004 Oct 1;130A(2):172–5.
6.         Bernbeck B, Schwabe J, Groninger A, Schaper J, Messing-Jünger H, Mayatepek E, et al. Aplasia cutis congenita of the scalp: how much therapy is necessary in large defects? Acta Paediatr. 2005 Jun;94(6):758–60.
7.         Rhee ST, Colville C, Buchman SR, Muraszko K. Complete osseous regeneration of a large skull defect in a patient with cutis aplasia: a conservative approach. J Craniofac Surg. 2002 Jul;13(4):497–500.
8.         Kalina MA, Kalina‐Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marszał E, et al. Do children with Adams‐Oliver syndrome require endocrine follow‐up? New information on the phenotype and management. Clinical Genetics. 2010 Sep 1;78(3):227–35.