Dubowitz Syndrome

Having in mind the fact that about 145 cases have been described in the literature so far, Dubowitz syndrome is a rare clinical entity with an unknown etiology [1] [2] [3]. Certain authors hypothesize that a genetic background (DNA ligase IV and RNA methyltransferase mutations), an autosomal recessive pattern of inheritance, and various hormonal abnormalities are involved in the pathogenesis [4] [5] [6]. Fortunately, the clinical presentation has been well-demarcated by several authors, and is composed of the following [1] [2] [3] [4] [5] [6]:

• Facial changes - One of the cardinal features of Dubowitz syndrome is a narrow and triangular-shaped face with micrognathia, a sloping forehead, and thin and sparse eyebrows and hair [1] [4]. Other common findings are low-set ears, wide-set eyes with drooping upper eyelids, a broad and wide nasal bridge, and facial asymmetry [1] [2] [3] [4]. Telecanthus, visual deficits, a cleft palate and several other facial deformities are less commonly encountered [1] [2] [3] [4].
• Growth abnormalities - In addition to a distinct facial appearance, a markedly reduced growth rate starting during intrauterine life is one of the main characteristics of Dubowitz syndrome [1] [2] [4] [5]. Virtually all individuals suffer from microcephaly, a short stature and a low body weight for appropriate age, whereas hypotonia (stemming from the weakness of the skeletal muscles) is also a frequent finding [1]. Furthermore, scoliosis, fused vertebrae, impaired rib development, toe fusion and feet-related problems (club foot, inverted foot, flat-footedness, etc.) are seen in a significant number of cases [1] [7].
• Psychiatric symptoms - Hyperactivity, aggressiveness, bedwetting, difficulties with sleep, and frequent withdrawal from other individuals or crowd (although rare) are often reported in Dubowitz syndrome [1] [3] [4]. A variable degree of mental retardation and learning impairment is observed as well [1] [3].

Other notable features are a high-pitched voice, gastrointestinal irritation (presenting as diarrhea), the presence of eczema, genital disorders (cryptorchidism, hypospadias, and underdevelopment of either male or female genitalia), frequent infections (most commonly of the ears, GI system, the lungs, the urinary tract and the sinuses), and several congenital heart diseases (atrial and ventricular septal defects, as well as patent ductus arteriosus) [1] [2] [3] [4]. Rare reports have described malignant tumors (primarily of hematologic origin), aplastic anemia and immunological deficits (IgA deficiency) [1] [3].

In the absence of clear diagnostic criteria for Dubowitz syndrome and the striking similarity to several other disorders (including Fanconi anemia, fetal alcohol syndrome, Bloom's syndrome, Nijmegen breakage syndrome), the diagnosis might be difficult to make. With a properly obtained patient history and a meticulous physical examination, a presumptive diagnosis can be made [1] [4]. Exposure to significant amounts of alcohol during intrauterine life should be addressed during history taking, whereas a familial occurrence of the syndrome has been reported in a small number of cases, suggesting that a complete family history might also be of benefit [1] [2] [4]. The physical examination is, however, the pivotal step in the diagnostic workup, as the diagnosis relies on recognition of clinical features [3]. A comprehensive assessment of facial changes and growth rate, evaluation of cognitive skills, and determination of additional defects is crucial [1] [4]. Depending on the presence of additional signs and symptoms, appropriate diagnostic procedures should be employed. For example, echocardiography is needed in the setting of congenital heart diseases (CHDs), whereas a complete laboratory workup with an immunological profile in case frequent infections is noted, or if there is valid clinical suspicion toward a malignant disease.

1. Huber RS, Houlihan D, Filter K. Dubowitz Syndrome: A Review and Implications for Cognitive, Behavioral, and Psychological Features. J Clin Med Res. 2011;3(4):147-155.
2. Lee MK, Lee YS. Anesthesia of a patient with Dubowitz syndrome -A case report-. Korean J Anesthesiol. 2010;58(5):495-499.
3. Turkbeyler IH, Pehlivan Y, Comez G, et al. Esophagus cancer and IgA deficiency in a patient with Dubowitz syndrome: a case report. Tokai J Exp Clin Med. 2011;36(2):29-30.
4. Chehade C, Awwad J, Yazbeck N, et al. Dubowitz syndrome: common findings and peculiar urine odor. Appl Clin Genet. 2013;6:87-90.
5. Yue J, Lu H, Lan S, et al. Identification of the DNA Repair Defects in a Case of Dubowitz Syndrome. Borgmann K, ed. PLoS One. 2013;8(1):e54389.
6. Martinez F, Lee JH, Lee JE, et al. Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet. 2012;49(6):380-385.
7. Ballini A, Cantore S, Tullo D, Desiate A. Dental and craniofacial characteristics in a patient with Dubowitz syndrome: a case report. J Med Case Reports. 2011;5:38.