Author: Manal Mirreh, MD – Children's Hospital of Philadelphia, Philadelphia, PA
A 2-month-old full-term boy with polysyndactyly/syndactyly/nail hypoplasia of the left foot, aplasia cutis, and cutis marmorata telangiectasia congenita presents to cardiology clinic for routine follow-up of a patent ductus arteriosus (PDA). His initial echocardiogram on day of life two showed bidirectional flow in his PDA, with normal RV pressure. His new echocardiogram now indicates suprasystemic right ventricular pressure, RV dysfunction and possible multivessel pulmonary vein disease. Given the physical exam and echocardiogram findings, which of the following genetic syndromes is the MOST likely present in this patient?
EXPLANATION
If a patient presents with skin (scalp) and limb defects plus signs of pulmonary hypertension, Adams-Oliver syndrome (AOS) should be considered.
Adams-Oliver Syndrome is a rare genetic disorder characterized by a distinct combination of congenital anomalies. The hallmark features include aplasia cutis congenita, most often presenting as areas of missing skin on the scalp, and transverse limb defects, such as missing digits, hypoplastic nails, or syndactyly. Many patients also exhibit cutaneous and vascular abnormalities, including cutis marmorata telangiectatica congenita (CMTC). CMTC is a rare congenital disorder characterized by discolored patches of skin caused by widened (dilated) surface blood vessels. As a result, the skin has a purple or blue “marbled” or “fishnet” appearance (cutis marmorata). Importantly, cardiovascular involvement is common and may include congenital heart defects as well as pulmonary hypertension, which is thought to arise from underlying vascular dysplasia.1 The syndrome can follow an autosomal dominant or recessive inheritance pattern, with mutations in genes such as ARHGAP31, DOCK6, and NOTCH1 identified in affected individuals.2
Cutis marmorata is a common benign reticulate marbling of the skin described in neonates. It represents a physiologic phenomenon, with exacerbation on exposure to cold and resolution with re-warming.
It remains somewhat unclear as to whether the prognosis of AOS without lethal anomalies alters the lifespan. However, it is very likely that limited forms of the disease with only skin and skeletal abnormalities are likely to be associated with a better prognosis and no reduction in lifespan as compared to those patients with systemic involvement.3
Holt-Oram syndrome is caused by mutations in the TBX5 gene and follows an autosomal dominant inheritance pattern. It is characterized primarily by abnormalities of the upper limbs, which can range from missing or malformed thumbs to more severe reductions of the long bones, such as phocomelia. These limb anomalies are usually bilateral but often asymmetric. A hallmark of Holt-Oram syndrome is its strong association with cardiac defects, especially atrial and ventricular septal defects, as well as cardiac conduction abnormalities ranging from first-degree heart block to more serious rhythm disturbances. Notably, patients with Holt-Oram syndrome do not exhibit scalp defects or intellectual disability.
Alagille syndrome is an autosomal dominant disorder consisting of bile duct paucity, cholestasis, “triangular” facies, widespread vascular anomalies, and congenital heart disease. The congenital heart disease commonly presents as peripheral pulmonary arterial stenosis or hypoplasia or pulmonary valve stenosis.
REFERENCES
1. Zapata, H.H., Sletten, L.J. and Pierpont, M.E.M. (1995), Congenital cardiac malformations in Adams-Oliver syndrome. Clinical Genetics, 47: 80-84. https://doi.org/10.1111/j.1399-0004.1995.tb03928.x
2. MedlinePlus Genetics. Adams-Oliver Syndrome. National Library of Medicine. Updated February 28, 2024. Accessed May 10, 2025. https://medlineplus.gov/genetics/condition/adams-oliver-syndrome/
3. Seo JK, Kang JH, Lee D, Sung HS, Hwang SW. A case of Adams-Oliver syndrome. Ann Derm 2010; 22:96-8.
