Visual Diagnosis: A Case of Stretchy Skin and Vascular Abnormalities

A 14-month-old boy is referred to our clinic after his parents noted that he had stretchy skin and looked thinner than his siblings did at his age.The patient was born to a 32-year-old gravida 3 para 3 woman in Saudi Arabia. The pregnancy was complicated by maternal hypertension and gestational diabetes. He was born by cesarean delivery at term gestation due to maternal hypertension. There was no premature onset of labor, bleeding, or leakage of amniotic fluid. The mother reports that he seemed fine in the newborn nursery. He had no difficulty breathing; however, he had asymptomatic bilateral inguinal hernias and a minor diaphragmatic hernia, all of which were repaired when he was 2 weeks of age without complications. At the time of his surgery, a heart murmur was found, and echocardiography revealed that he had a dilated ascending aorta. There were no vision or hearing concerns. He did not have any feeding or developmental problems. The patient’s family history reveals that the patient’s maternal grandfather and father are first cousins. The patient has 2 first cousins who had surgical correction of vascular abnormalities. A maternal grandmother had multiple valve operations as an adult. There is no history of aortic dissection or rupture.On physical examination his height is 31.6 in (80.2 cm) (81st percentile) and weight is 22.7 lb (10.3 kg) (57th percentile). The patient’s blood pressure is 125/35 mm Hg, heart rate is 115 beats/min, and temperature is 97.9°F (36.6°C). The patient is in no apparent distress and is breathing comfortably. A normal precordial impulse is present, with normal S1 and S2 sounds, and no gallops or rubs are noted. A high-pitched late systolic ejection murmur is heard at the left upper sternal border. The murmur radiates to the left lung. There is hyperextensibility and excessive wrinkling of the patient’s hands, as well as slight redundancy of the skin on his face and lower sacrum. There are no rashes, bruises, or petechiae. The patient has dysmorphic facial features with mild blepharophimosis, periorbital fullness, down-slanting palpebral fissures, mild malar hypoplasia, a somewhat beaked nose, and extended lower lip. The head is brachycephalic and appears broad. The ears are formed normally but with decreased cartilage and excessive pliancy. Mild joint laxity is noted, but the thorax is without deformity or scoliosis. The remainder of the physical examination findings are within normal parameters.A chest radiograph reveals levocardia with normal-sized abdominal viscera and a dilated aortic root (Fig 1). Further imaging and genetic testing in the context of the patient’s physical examination findings confirm the diagnosis.The lungs are clear, and there are no noticeable abnormalities of the cardiac border. Computed tomography angiography reveals a dilated aortic root at the level of the sinus of Valsalva that measures 24 mm. The number of standard deviations above the population mean or z score of the aortic root measurement is 6.24. The main pulmonary arteries are narrow and moderately tortuous, with multiple 90° turns (Figs 2 and 3). The genetic counselor constructs the pedigree from a detailed family history (Fig 4). Genetic testing reveals a loss-of-function mutation in the SLC2A10 gene, which encodes for the glucose transporter GLUT10. The imaging studies and genetic testing were consistent with arterial tortuosity syndrome (ATS).ATS is a rare genetic syndrome, first described in 1976, affecting girls and boys in equal numbers. Approximately 100 cases have been reported in the medical literature, although the exact incidence and prevalence of the disease is unknown. (1) The onset of the disease is typically in early infancy or childhood, with many misdiagnosed or undiagnosed cases. Patients may present in infancy with soft redundant skin, diaphragmatic hernia, or vascular abnormalities. The aberrant gene mutation in ATS is found in SLC2A10 encoding for the glucose transporter GLUT10. The mode of inheritance is autosomal recessive involving chromosome 20. (2)The major clinical features of this disease include tortuosity and elongation of major vasculature with an increased risk of aneurysms, dissections, and stenosis of aorta or pulmonary arteries. Patients are susceptible to thrombosis, as well as systemic and pulmonary hypertension. There have been reported cases of an aberrant origin of the aortic branches or coarctation of the aorta. An additional disease manifestation is vasomotor instability with a Raynaud phenomenon. It is often recommended that individuals with ATS have comprehensive magnetic resonance angiography to assess vasculature. Less common manifestations of ATS include tracheomegaly, tracheomalacia, and bladder or kidney diverticula.Characteristic craniofacial features suggest the diagnosis of this syndrome, which may include a somewhat elongated face, short palpebral fissures that are down-slanted, malar hypoplasia, a somewhat aged appearance, velvety hyperextensible skin that can improve with age, inguinal hernias, pectus deformity, scoliosis, joint laxity, or contractures.Patients with ATS may also develop corneal abnormalities, such as keratoglobus, that result in deterioration of their vision. To date there has been only 1 reported case of keratoglobus in a patient with ATS, although it is commonly associated with other inheritable disorders, such as Ehlers-Danlos syndrome type IV, blue sclera syndrome, and Leber congenital amaurosis.ATS is a disorder characterized by a genetic mutation, inherited in an autosomal recessive pattern, resulting in a loss of function of the GLUT10 transporter. The exact mechanism by which this mutation results in disease is not fully understood. There are 2 possible theories that have been proposed to date. First, the GLUT10 transporter dysfunction results in a diminished glucose-responsive transcription of decorin, which is a known inhibitor of the transforming growth factor-β (TGF-β) signaling pathway. Abnormalities in the TGF-β signaling pathway are also implicated in other heritable connective tissue disorders, such as arterial tortuosity in Loeys-Dietz syndrome and thoracic aortic aneurysm and dissections in Marfan syndrome. Second, the GLUT10 protein is responsible for the regulation of sugars, including the precursor of vitamin C (dehydroascorbic acid), across cells. The mutation in the transporter may result in a possible decrease of vitamin C in cells, resulting in abnormal collagen or elastin synthesis. The vascular histopathology in patients with ATS shows fragmentation of the internal elastic membrane and disruption of elastic fibers of the tunica media. (1)There are multiple shared characteristics with other heritable connective tissue disorders, such as hyperextensible skin, cutis laxa, dysmorphic facial features, keratoconus/keratoglobus, hernias, joint hypermobility and instability, and skeletal anomalies. (2) The differential diagnosis of ATS should include Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and Marfan syndrome (Table). The hypothesis that ATS involves a genetic mutation affecting the TGF-β signaling pathway overlaps with the pathophysiology present in Loeys-Dietz syndrome and neonatal Marfan syndrome. In addition, in the differential diagnosis are recessive forms of cutis laxa, such as due to the fibulin-4 gene, that also can be associated with similar clinical features and the aortic dilatation.The management of ATS includes a coordinated approach from multidisciplinary specialists and regular cardiovascular follow-up for appropriate surveillance. A treatment plan should be tailored to the individual patient based on vascular imaging, rate of progression, and perceived risks. (3) For treatment, an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker should be considered to reduce hemodynamic stress on the arterial wall and slow the rate of aortic root dilation, particularly with hypertensive children. The timing of surgical consideration may relate to the presence or absence of other vascular anomalies as well as the size of his aorta or the rate of progression. Ophthalmologic examination is recommended to look for anomalies that are sometimes associated with ATS, such as keratoconus, astigmatism, or myopia. The kidneys should be evaluated with ultrasound to identify any vascular anomalies or complications.The science of medical genetics is changing particularly rapidly at this time. All individuals with known or suspected genetic disorders may benefit from an updated consultation every few years, especially if significant changes occur in the patient's medical condition or in the family history.There is an increased risk of systemic symptoms and sudden death due to acute respiratory insufficiency or cardiac failure in children. Early diagnosis is essential to ensure appropriate clinical management and decreased risk of fatal complications. In the older medical literature, it was stated that mortality at age 18 years was up to 40%, although subsequent reports indicate better survival. Nonetheless, this is a very serious disorder with multiple risks.At 4 years of age, the patient was doing well with continued surveillance. Computed tomography angiography revealed that the aortic root had further dilated to 32 mm (z score = 7.88), and the patient had a bout of rectal prolapse. As the patient grew older, he reported decreased vision and was referred to an ophthalmologist. The patient was found to have a diffusely thin cornea and posterior stromal haze characteristic of keratoglobus. His myopia and visual acuity were corrected with glasses.Features associated with this syndrome that could have a life-threatening impact include pulmonary hypertension and aortic dilation with possible risk of complication if not managed or kept under surveillance. The patient was given an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker to reduce the risk of hemodynamic stress on the arterial wall and prevent further aortic dilation. Indications for future surgical or transcatheter intervention would include decreased right ventricular function, ongoing aortic enlargement beyond 40 to 45 mm, or progression of his aortic insufficiency. The patient remains on medical management and has biannual surveillance appointments with his pediatric cardiologist.Note: This case is based on a poster presentation by Simrit K. Warring, MS, Richmond Castillo, MS, Kelsey Klaas, MD, Nathaniel Taggart, MD, Philip R. Fischer, MD, at the 2016 American Academy of Pediatrics National Conference & Exhibition, San Francisco, CA. Poster Session: Section of Pediatric Trainees, Presentation Date: October 2016, Poster Number: 4.