Isotretinoin Embryopathy-Like Syndrome

Multiple congenital anomalies, prominently including malformations of the head and face (small, malformed, or missing ears, micrognathia, and cleft palate), heart (particularly conotruncal defects and aortic arch anomalies), and central nervous system (especially hydrocephalus and posterior fossa abnormalities), result from maternal use of isotretinoin, a vitamin A analog for treatment of acne (Benke, 1984; Braun et al., 1984; Lott et al., 1984; Lammer et al., 1985). The associated anomalies are also consistent with those described for excessive maternal vitamin A use. Kawashima et al. (1987) described 3 male sibs with findings consistent with isotretinoin embryopathy; each had malformations of the ears and an interrupted aortic arch. The mother of the patients, however, had no prenatal history of exposure to isotretinoin, and her diet was not unusual. The patients had normal lymphocytes and serum calcium values, making the diagnosis of DiGeorge syndrome (188400) untenable.

Guion-Almeida et al. (2000) described a Brazilian boy with the same abnormalities as those described by Kawashima et al. (1987), although middle and inner ear defects were also present. Guion-Almeida and Kokitsu-Nakata (2003) described a single case. Their patient had a complex heart defect, and computed tomography of the temporal bone showed agenesis of the external auditory canal on the left and ossicular chain abnormalities bilaterally. All 5 reported cases have been in males, and parental consanguinity was not described in any. All 5 patients died before the second year of life.

Derbent et al. (2005) reported a male patient with right microtia, atresia of the external auditory canal, growth retardation, a complex heart defect, and extra-lobar pulmonary sequestration. The cardiac anomalies were persistent left superior vena cava, aortic stenosis, bicuspid aortic valves and subaortic membrane. Spinal films revealed complete fusion of the C2-C3 and C5-C6 vertebrae, and scoliosis of the lumbar spine. The patient's mental development was normal, and there were no abnormalities on ophthalmologic examination. Derbent et al. (2005) suggested that their patient and 5 previously reported patients (Kawashima et al., 1987; Guion-Almeida et al., 2000; Guion-Almeida and Kokitsu-Nakata, 2003) had a variant of the oculoauriculovertebral spectrum, with the cardinal features of microtia, atresia of the external auditory canal, complex cardiac defects, growth retardation, normal mental and motor development in most cases, and vertebral anomalies. Because all 6 patients were male, Derbent et al. (2005) raised the possibility of X-linked inheritance.