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].

• 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]

• 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]

• 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]

  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 [symptoma.com]

  Symptoms and Signs Symptoms largely vary among different patients, however other characteristics may include a soft but high pitched voice, webbing of fingers and toes but not totally, deformations of the palate, some abnormalities in the genitalia, eczema [medigest.uk]

  These include a high-pitched voice, genital abnormalities including undescended testicles, gastroesophophageal reflux (returning food back from the stomach to the mouth), and inflammation and itching of the skin. [poandpo.com]

• Failure to Thrive

  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]

  The clinical features include short stature, failure to thrive, microencephaly, micrognathia, retrognathia, mild intellectual disabilities, and eczema. Synonym Intrauterine Dwarfism. [accessanesthesiology.mhmedical.com]

  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]

• Unilateral Ptosis

  Relative hypertelorism (outer canthus to outer canthus 9.5 cm [95th percentile]) was noted and unilateral ptosis with upslanted palpebral fissures. [healio.com]

• Alopecia

  McPherson Clemens syndrome Malignant hyperthermia susceptibility type 3 Oslam syndrome L-arginine:glycine amidinotransferase deficiency Lin-Gettig syndrome Alopecia-intellectual disability syndrome Tabatznik syndrome Persistent Mullerian duct syndrome [checkrare.com]

• Short Attention Span

  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 may include hyperactivity with short attention span, impulsivity and shyness. [orpha.net]

  Patients are often described as hyperactive with a short attention span (67%), stubborn, and shy. Muscular hypotonia is common (40%). Seizures are rare. [accessanesthesiology.mhmedical.com]

  Behavioral characteristics include hyperactivity, short attention span, and aggressiveness. Behavior problems include difficulty feeding, sleep disturbance, and bedwetting. [cornerstone.lib.mnsu.edu]

• Impulsivity

  Behavioral characteristics may include hyperactivity with short attention span, impulsivity and shyness. [orpha.net]

  Hyperactivity can exacerbate impulsiveness, problem behaviors, and learning deficits. Frequent outbursts are not uncommon in these children [ 5 ]. [ncbi.nlm.nih.gov]

• Psychiatric Symptoms

  Psychiatric symptoms - Hyperactivity, aggressiveness, bedwetting, difficulties with sleep, and frequent withdrawal from other individuals or crowd (although rare) are often reported in Dubowitz syndrome. [symptoma.com]

• Small Face

  Craniofacial anomalies may include microcephaly (with head circumference below the third percentile), premature craniosynostosis, distinctive, small face with high forehead, flat supraorbital ridge, short palpebral fissures, scanty or absent lateral part [accessanesthesiology.mhmedical.com]

  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]

  […] retarded Short 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 [syndrome.org]

  […] jaw Small lower jaw [ more ] 0000347 Narrow face Decreased breadth of face Decreased width of face [ more ] 0000275 Postnatal growth retardation Growth delay as children 0008897 Protruding ear Prominent ear Prominent ears [ more ] 0000411 Ptosis Drooping [rarediseases.info.nih.gov]

• 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]

• Hyperactivity

  […] 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]

  Characteristic behavior patterns which have not been cited previously are present in our cases; most patients are hyperactive, shy, hate crowds, and like music, rhythm, and vibrations from music speakers, tape recorders, or transmitted through floors. [ncbi.nlm.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 [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.

• 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]

The complications of Dubowitz Syndrome may include: Development of cancer Neurological impairment Emotional stress due to cosmetic concerns Complications may occur with or without treatment, and in some cases, due to treatment also. [dovemed.com]

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]

Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology. [icd10coded.com]

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. [symptoma.com]

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]

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]

[…] study examined the specific oral features in one patient. [10] Another found abnormalities in the brain, such as corpus callosum dysgenesis, an underdeveloped anterior pituitary and a brain stalk with an ectopic (misplaced) posterior pituitary. [11] Epidemiology [en.wikipedia.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]

Mutations in the DHCR7 gene reduce or eliminate the activity of this enzyme, preventing cells from producing sufficient cholesterol [ 23, 24 ]. [jmedicalcasereports.biomedcentral.com]

If severe enough a tracheostomy may be performed to help prevent complications such as aspiration of food into the lungs or infections. [bertsbigadventure.org]

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.