An Infant With Congenital Scalp, Nail, and Limb Anomalies

An 11-day-old term female was referred for anonychia. On examination, she had anonychia of most toenails with micronychia of the right great toe (Figure 1), circular atrophic plaques over the scalp (Figure 2), a generalized reticulate, bluish-purple patch that did not disappear with warming (Figure 3), and hypoplastic digits on both feet with 2–3 syndactyly bilaterally (Figure 1). Family history was significant for aplasia cutis congenita (ACC) in her father. There was no consanguinity. Echocardiography revealed mild pulmonic stenosis that did not require intervention. Diagnosis: Adams-Oliver Syndrome. The combination of ACC, terminal transverse limb defects (TLD), and cutis marmorata telangiectatica congenita (CMTC) are classic features of Adams-Oliver Syndrome (AOS). Diagnosis is based on either the presence of two major criteria or one major and one minor criterion. Major criteria include TLDs, ACC, and a positive family history, while minor criteria include CMTC, congenital heart defects, and vascular anomalies [1]. Our patient met clinical criteria for diagnosis. Genetic testing in our patient was negative for mutations in the 6 genes associated with AOS. AOS is a rare congenital disorder estimated to occur in 1 in 225,000 live births [2]. Several pathogenic variants have been implicated in AOS, including genetic alterations in ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, and RBPJ, important genes in embryonic developmental pathways [2]. However, causative genetic variants are only found in approximately 30% of cases of AOS [2]. Although scalp and limb abnormalities are characteristic of AOS, there is variable expressivity with differing presentation and severity. ACC can range from small areas of skin atrophy to deeper and more severe lesions [3]. TLDs are also common in AOS and can vary from hypoplastic nails to complete absence of the distal limbs [4]. Brachydactyly, the shortening of fingers or toes, is the most frequently described limb malformation but syndactyly, polydactyly, and oligodactyly may also be observed [4]. These extremity abnormalities usually affect both sides with differing severity and often involve the lower extremities [4]. Patients may also present with other associated abnormalities, with CMTC present in 25% of reported cases [5]. Extracutaneous involvement includes ocular abnormalities, such as congenital cataracts and retinal detachment; cardiac malformations, such as septal defects; and gastrointestinal anomalies, including hepatoportal disease and portal hypertension [2, 6, 7]. The severity and combination of these malformations can vary significantly. Most patients with AOS present with autosomal dominant inheritance, but autosomal recessive and sporadic forms have also been reported [2]. Pathogenic variants in multiple genes explain the variation in this disease's phenotypic expression [2]. Heterozygous pathogenic variants in ARHGAP31, RBPJ, NOTCH1, or DLL4 have been found in autosomal dominant and sporadic cases, while autosomal recessive forms of AOS may be due to biallelic pathogenic variants in DOCK6 or EOGT [2]. The RBPJ, NOTCH1, DLL4 and EOGT genes are part of the Notch signaling pathway and are involved in cell proliferation and cell death and ARHGAP31 and DOCK6 contribute to the maintenance of the actin cytoskeleton [8]. Notably, a loss-of-function pathogenic variant in NOTCH1 has been found in the majority of autosomal dominant cases of AOS [2]. Cardiac anomalies were more commonly seen in patients with a NOTCH1, DLL4, or RPBJ pathogenic variant [2]. Similarly, a positive correlation was found between patients with recessive pathogenic variants in DOCK6 and the presence of neurological abnormalities [2]. In our case, the patient's father exhibited symptoms characteristic of AOS, including a small scalp defect at the vertex and spoon-shaped broad fingers and thumbs. Clinical analysis of multiple families with AOS revealed that the parents and siblings of affected patients often exhibit similar developmental abnormalities, primarily scalp and limb defects [9]. This complex genetic landscape highlights the need for comprehensive genetic testing in diagnosing and managing AOS, and for accurate genetic counseling to affected families. While clinical criteria help establish a diagnosis of AOS, other conditions may present with similar features. The differential diagnosis includes epidermolysis bullosa; sebaceous nevus, central nervous system malformations, ACC, limbal dermoid, and pigmented nevus (SCALP) syndrome; and amniotic band syndrome. Epidermolysis bullosa can present with scalp defects and nail dystrophy but has distinctive skin fragility and bullae formation [5]. SCALP syndrome has ACC but presents with congenital melanocytic nevi, nevus sebaceus, and a higher risk of perinatal death. Amniotic band syndrome is another congenital syndrome that can result in limb abnormalities but is distinct from AOS in its absence of ACC or CMTC [10]. Management of AOS is multidisciplinary and involves geneticists, dermatologists, cardiologists, and various social support networks [10]. Plastic and orthopedic surgery may be needed for the hypoplastic limb defects and ACC [5, 10]. Patients should receive an echocardiogram and a detailed ophthalmologic exam. A brain MRI may be considered in cases with neurologic involvement or underlying skull defects and an abdominal ultrasound can screen for structural liver and kidney anomalies [10]. Most patients are expected to live a normal life [5]. This case highlights the importance of a thorough clinical examination and family history in patients presenting with scalp, nail, and limb defects. Early recognition can initiate prompt genetic testing and screening for internal organ involvement. Dermatologists can play a key role in the early identification and referral of AOS patients. Authors made significant contributions to study conception and design, data collection, analysis and interpretation of results, and draft manuscript preparation. All authors read and approved the final version. The authors declare no conflicts of interest.

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