Dubowitz syndrome is a rare disease presenting with microcephaly, several facial abnormalities, growth retardation and a variable degree of mental changes. The diagnosis rests on the ability of the physician to recognize the main signs and symptoms, as clear diagnostic criteria do not exist.
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   . 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   . Fortunately, the clinical presentation has been well-demarcated by several authors, and is composed of the following      :
- 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  . Other common findings are low-set ears, wide-set eyes with drooping upper eyelids, a broad and wide nasal bridge, and facial asymmetry    . Telecanthus, visual deficits, a cleft palate and several other facial deformities are less commonly encountered    .
- 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    . 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 . 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  .
- Psychiatric symptoms - Hyperactivity, aggressiveness, bedwetting, difficulties with sleep, and frequent withdrawal from other individuals or crowd (although rare) are often reported in Dubowitz syndrome   . A variable degree of mental retardation and learning impairment is observed as well  .
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)    . Rare reports have described malignant tumors (primarily of hematologic origin), aplastic anemia and immunological deficits (IgA deficiency)  .
Entire Body System
- Recurrent Infection
Eczema and recurrent infections require conservative treatment. Surgical intervention might be necessary for certain cardiovascular, urogenital, craniofacial or limb anomalies. Surveillance of hematological and malignant disorders is recommended. [orpha.net]
She/he may be prone to recurrent infections, hypogammaglobulinemia, IgA deficiency, aplastic anemia, acute lymphatic leukemia, lymphoma, and/or neuroblastoma. contributor: Kelly A.Przylepa, revised 4/4/2003 creation date: John F. [dubowitzsyndrome.net]
infections Frequent infections Frequent, severe infections Increased frequency of infection infections, recurrent Predisposition to infections Susceptibility to infection [ more ] 0002719 Respiratory insufficiency Respiratory impairment 0002093 Sandal [rarediseases.info.nih.gov]
- Poor Feeding
Dubowitz syndrome is a rare hereditary disorder whose main features are intra-uterine and post-natal growth retardation, characteristic facies, microcephaly, mental retardation and poor feeding. [ncbi.nlm.nih.gov]
Abdominal/Gastrointestinal characteristics can include poor feeding, frequent vomiting, chronic diarrhea, and/or gastroesophageal reflux. In boys, there can be hypospadias, inguinal hernia, or cryptorchidism. [dubowitzsyndrome.net]
Associations have been made with hyperactivity (4G" variable clefts of the soft palate (10% to 15%), poor feeding and gastroesophageal reflux (33%), chronic diarrhea (35%), and mild eczema (65%)7. [healio.com]
Here we describe a male Turkish patient who has typical and less common findings of DS with additionally persistently low serum lipid levels and an arachnoid cyst. The present patient is the second case of DS with persistently low cholesterol levels. [ncbi.nlm.nih.gov]
- High Pitched Voice
Speech delays, an unusually soft, high-pitched voice, submucous cleft palate, and velopharyngeal insufficiency were noted in childhood. Mild mental retardation was present. [ncbi.nlm.nih.gov]
Symptoms vary among patients, but other characteristics include a soft, high-pitched voice, partial webbing of the fingers and toes, palate deformations, genital abnormalities, language difficulties, and an aversion to crowds. ". Arch. Fr. Pediatr. [en.wikipedia.org]
- Nasal Voice
These features and other very common ones are listed below: Common clinical features of DS Eczema or eczema-like skin rash (early years especially) High-pitched nasal voice (may also be hoarse) Very short stature (often Poor weight gain in the early years [forgottendiseases.org]
- Failure to Thrive
Afterwards, the child is sometimes labeled as failure to thrive. The head is usually microcephalic and face is small with some elongation with age. [dubowitzsyndrome.net]
Failure to Thrive : growth failure, or failure to thrive (FTT), is a descriptive term and not a specific diagnosis. Although definitions vary, most use this term only when growth has been noted to be low or to have decreased over time. [ric.edu]
On the other hand, lack of eating has been associated with failure to thrive or anorexic-like tendencies [ 12, 21, 29 ]. Failure to thrive is associated with a child’s inability to gain weight, grow or feed normally [ 29 ]. [ncbi.nlm.nih.gov]
The clinical features include short stature, failure to thrive, microencephaly, micrognathia, retrognathia, mild intellectual disabilities, and eczema. Synonym Intrauterine Dwarfism. [accessanesthesiology.mhmedical.com]
- Short Attention Span
Behavioral characteristics may include hyperactivity with short attention span, impulsivity and shyness. [orpha.net]
Also described is a tendency to be hyperactive or to have a short attention span. Speech delay is also common, as is a high pitched or nasal-y voice. The child's biggest issues seem to be with the immune system. [dubowitzsyndrome.net]
attention span Shyness Mental retardation mild to severe Stubbornness Short attention span Reduced muscle tone Small face Supraorbital ridge is swallow Head that is small Short palpebral fissures Tip of nose broad Flat nasal bridge Lateral telecanthus [syndrome.org]
Behavioral characteristics include hyperactivity, short attention span, and aggressiveness. Behavior problems include difficulty feeding, sleep disturbance, and bedwetting. [cornerstone.lib.mnsu.edu]
Face, Head & Neck
- Small Face
For example, many people affected by the disease have a small face and head. Sometimes they have a high forehead that slopes as well. In many cases, the eyelids droop and the nose is wide and flat. [wisegeek.net]
Affected individuals have small face which is often triangular in shape with a pointed, receding chin. They also have broad wide-tipped nose, broad and sloping forehead, and wide-set eyes with drooping eyelids. [brighthub.com]
face Supraorbital ridge is swallow Head that is small Short palpebral fissures Tip of nose broad Flat nasal bridge Lateral telecanthus Drooping upper eyelid Eyes are wide-set Blepharophimosis Prominent ears Epicanthal folds Dysplastic ears that is mild [syndrome.org]
face Short and narrow face Small facies [ more ] 0000274 Syndactyly Webbed fingers or toes 0001159 Velopharyngeal insufficiency Velopharyngeal incompetence 0000220 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened nasal bridge Increased [rarediseases.info.nih.gov]
face Tapetoretinal degeneration Velopharyngeal insufficiency Wide nasal bridge Based on the frequency of symptoms observed, the following information may be noted: Very frequently present symptoms in 80-99% of the cases: Aplasia/hypoplasia of the thumb [dovemed.com]
- High Sloping Forehead
Dubowitz syndrome (DS) (MIM#223370) (4) is a very rare genetic and developmental disorder involving multiple congenital anomalies including: 1) growth failure/short stature; 2) unusual but characteristic facial features; small triangular face, high sloping [ncbi.nlm.nih.gov]
Other facial characteristics can include a shallow supraorbital ridge, asymmetry, micrognathia, dysmorphic features, and a high, sloping forehead. [dubowitzsyndrome.net]
sloping forehead, drooping eyelid, short distance between the inner and outer corner of the eye, broad and flat nasal bridge), microcephaly, intellectual disability, and eczema. [dovemed.com]
This autosomal recessive disorder is characterized by variable degrees of intrauterine and postnatal growth retardation, microcephaly, mild mental retardation, hyperactivity, "eczema", characteristic facial appearance and combination of minor abnormalities [ncbi.nlm.nih.gov]
[…] disorder Attention deficit Attention deficit disorder Attention deficit-hyperactivity disorder Attention deficits Childhood attention deficit/hyperactivity disorder [ more ] 0007018 Blepharophimosis Narrow opening between the eyelids 0000581 Clinodactyly [rarediseases.info.nih.gov]
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  . 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   . The physical examination is, however, the pivotal step in the diagnostic workup, as the diagnosis relies on recognition of clinical features . A comprehensive assessment of facial changes and growth rate, evaluation of cognitive skills, and determination of additional defects is crucial  . 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.
- Delayed Bone Age
Analysis of approximately 30 cases reveals prevalence of growth failure and delayed bone age, mild microcephaly, broad forehead with sparse frontal hair, telecanthus, blepharophimosis, abnormal pinnae, broad nose, and micrognathia. [ncbi.nlm.nih.gov]
Skeletal issues can be delayed bone age, fifth finger clinodactyly, two/three toe syndactyly, and pes planus. Some are very prone to eczema or have severe allergies. There also can be sacral dimple (s), sparse scalp hair, and some hypotonia. [dubowitzsyndrome.net]
bone age. head: microcephaly; high forehead; sparse hair; broad nose; epicanthus; hypertelorism; blepharophimosis; microretrognathia. skin: eczema, a classical sign, may be absent. congenital heart defects in 10%; other malformations: ocular, dental, [atlasgeneticsoncology.org]
Skeletal issues can be delayed bone age, fifth finger clinodactyly, two/three toe syndactyly, and pes planus. Some are very prone to eczema or have severe allergies. There also can be sacral dimple(s), sparse scalp hair, and some hypotonia. [ric.edu]
The pediatric dentist should possess the ability to recognize this rare alteration, to provide dental treatment and to refer for the necessary medical and multidisciplinary treatment. [ncbi.nlm.nih.gov]
Management and treatment Growth, dental speech, behavioral and intellectual development and a general health status check should be monitored regularly and treated appropriately. Eczema and recurrent infections require conservative treatment. [orpha.net]
Treatment Like most genetic disorders, Dubowitz syndrome has no medical treatment but there are treatment options to lessen the severity of the symptoms. [brighthub.com]
Prognosis The prognosis is very variable depending on the severity and types of congenital anomalies present and the long-term outcome still remains elusive, as no data is available after puberty. [orpha.net]
Prognosis Concerning the prognosis for individuals with this syndrome it is very good providing that the managing of medical situations is continued. [syndrome.org]
Prognosis The prognosis of individuals affected with Dubowitz syndrome is good as long as the management of symptoms is maintained. They can survive to adulthood and lead fairly normal lives, although some of them have mild mental retardation. [brighthub.com]
Etiology The etiology of Dubowitz syndrome has not been evidently elucidated. Two causal genes have been put forward in separate isolated cases and include NSUN2 and LIG4. [orpha.net]
Elsevier Health Sciences, ١٨/٠٨/٢٠١٣ - 979 من الصفحات Smith’s Recognizable Patterns of Human Malformation has long been known as the source to consult on multiple malformation syndromes of environmental and genetic etiology as well as recognizable disorders [books.google.com]
Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology. [icd10coded.com]
This suggested that a defect in telomere maintenance could be involved in the etiology of this disease. [journals.plos.org]
Summary Epidemiology The total birth prevalence in Europe has been estimated at 1/500,000. Over 150 cases have been described to date. Clinical description Newborns often have a low birth weight with a small head and body size. [orpha.net]
Epidemiology of fetal alcohol syndrome in a South African community in the Western Cape Province. Am J Public Health. 2000 Dec. 90(12):1905-12. [Medline]. May PA, Gossage JP, White-Country M, et al. [emedicine.medscape.com]
Epidemiological study of achalasia in children. Gut. 1988;29:90-93. Google Scholar | Crossref | Medline | ISI 8. Myers NA, Jolley SG, Taylor R. Achalasia of the cardia in children: a worldwide survey. J Pediair Surg. 1994;29:1375-1379. [journals.sagepub.com]
Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR (2004) Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 101: 281–288. View Article Google Scholar 40. [journals.plos.org]
Pathophysiology The precise mechanisms leading to the very wide phenotypic presentations of the syndrome remain to be determined. Diagnosis No biochemical characterization to confirm Dubowitz Syndrome is available. [accessanesthesiology.mhmedical.com]
[…] and classification of disorders of sex development To make a diagnosis, it is essential not only to understand normal development but also to understand the different pathophysiological mechanisms responsible for DSDs. [patient.info]
Related Medscape Reference topics: Focal Muscular Atrophies Spinal Muscle Atrophy Spinal Muscular Atrophy Related Medscape resource: Resource Center Spinal Disorders Pathophysiology Spinal muscular atrophy (SMA) is caused by successive motor unit degeneration [emedicine.medscape.com]
Currently, Dubowitz Syndrome may not be preventable, since it is a genetic disorder. [dovemed.com]
Am J Med Genet C Semin Med Genet a b Microcephaly Information Page at NINDS "Microcephaly – Symptoms, Treatment and Prevention". The HealthCentralNetwork. Archived from the original on 2007-05-13. [en.wikipedia.org]
Mutations in the DHCR7 gene reduce or eliminate the activity of this enzyme, preventing cells from producing sufficient cholesterol [ 23, 24 ]. [jmedicalcasereports.biomedcentral.com]
- 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.
- Lee MK, Lee YS. Anesthesia of a patient with Dubowitz syndrome -A case report-. Korean J Anesthesiol. 2010;58(5):495-499.
- 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.
- Chehade C, Awwad J, Yazbeck N, et al. Dubowitz syndrome: common findings and peculiar urine odor. Appl Clin Genet. 2013;6:87-90.
- 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.
- 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.
- 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.