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Dubowitz Syndrome

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.


Presentation

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]:

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]
  • 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.[ric.edu]
  • 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]
  • 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.[ric.edu]
  • 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]
Turkish
  • 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]
  • 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]
  • […] may be absent. congenital heart defects in 10%; other malformations: ocular, dental, skeletal, urogenital in male patients; frequent infections. mental retardation in 30-70 % of cases (from normal in 30% to severe retardation in 10%); siezures in 10%high-pitched[atlasgeneticsoncology.org]
Pneumonia
  • The hyper-immunoglobulin E (hyper-IgE or Job syndrome) is a primary immunodeficiency characterized by recurrent staphylococcal abscesses, recurrent cyst-forming pneumonia, and an elevated serum IgE level of 2000 IU/ml.[ncbi.nlm.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]
  • Other facial characteristics can include a shallow supraorbital ridge, asymmetry, micrognathia, dysmorphic features, and a high, sloping forehead.[ric.edu]
  • They include small head size, below average height and weight, high-pitched, hoarse voices, eczema and unusual facial features, like small lower jaws, drooping eyelids, high, sloping foreheads and an above average distance between eyes.[telegram.com]
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]
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]
  • Behavioral characteristics include hyperactivity, short attention span, and aggressiveness. Behavior problems include difficulty feeding, sleep disturbance, and bedwetting.[cornerstone.lib.mnsu.edu]
  • 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]
Hyperactivity
  • 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]
  • Further findings include hyperactivity, eczema, cryptorchidism in the affected males, and brachy-clinodactyly of the fifth fingers. Thirty-three cases with this syndrome have been reported in the literature. Five additional patients are presented.[ncbi.nlm.nih.gov]
  • Major clinical findings are intrauterine and postnatal growth retardation, considerable microcephaly, mild mental retardation, hyperactivity, hyperextensibility of joints, eczema and a characteristic appearance of the face due to marked epicanthic folds[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]
  • 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]
Irritability
  • A number of other symptoms, most commonly irritation and itching of the skin (eczema), may be present in infants born with Dubowitz syndrome.[web.archive.org]
  • 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]
  • There are a number of other symptoms which most commonly include irritation and itching of the skin. Dubowitz syndrome is passed on through an autosomal recessive pattern of inheritance.[poandpo.com]
  • A number of other symptoms, most commonly irritation and itching of the skin (eczema), may be present in infants born with Dubowitz syndrome. Genetic profile Dubowitz syndrome is passed on through an autosomal recessive pattern of inheritance.[encyclopedia.com]
Language Delays
  • delay Language delayed Language development deficit Late-onset speech development Poor language development Speech and language delay Speech and language difficulties Speech delay [ more ] 0000750 Episodic vomiting 0002572 Facial asymmetry Asymmetry[rarediseases.info.nih.gov]

Workup

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]

Treatment

  • 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]
  • A review of the literature and the surgical treatment of this patient is presented.[ncbi.nlm.nih.gov]
  • After detection of mutations in the PCNT gene, a full vascular status including cerebral imaging and cardiac evaluation needs to be determined in order to analyze vascular abnormalities and initiate prophylactic treatment.[ncbi.nlm.nih.gov]
  • 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

  • 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]
  • Prognosis Dubowitz syndrome prognosis is very good especially if there is continuous management of underlying medical problems. This condition had never caused shortening of a person’s lifespan or other worsening conditions.[syndromespedia.com]
  • Prognosis The prognosis for individuals affected by Dubowitz syndrome is good provided that management of their medical conditions is maintained. Dubowitz syndrome has not been reported to cause shortened lifespan or any degenerative conditions.[encyclopedia.com]

Etiology

  • 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]
  • 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]
  • Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology.[icd10coded.com]
  • The etiology of the cataracts is unknown, but the surface ectodermal derivation of the lens may point to the possibility of a gene related to connective tissue formation or regulation.[healio.com]

Epidemiology

  • 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]
  • […] adult patients with SMA type III or IV found that spinal cord gray matter had considerably atrophied between C2 and C6, while, possibly owing to an adaptive mechanism, the gray matter had grown denser in the motor and extramotor cortical regions. [5] Epidemiology[emedicine.medscape.com]
  • Epidemiology DSDs are caused by a variety of different conditions which vary greatly in incidence: Genital anomalies are estimated to occur in 1 in 4,500 births. [ 6 ] The most common cause of ambiguous genitalia in the newborn is congenital adrenal hyperplasia[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • […] 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]

Prevention

  • Growth Hormone Deficiency. 1979. 30 April 2007. 1 2 Microcephaly Information Page at NINDS "Microcephaly - Symptoms, Treatment and Prevention". The HealthCentralNetwork. Ahmad A, Amalfitano A, Chen YT, Kishnani PS, Miller C, Kelley R (1999).[ipfs.io]
  • It is hoped that this new knowledge will lead to prevention and treatment of genetic and familial disorders in the future. Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.[rarediseases.org]
  • Aside from treatment and prevention, identifying the gene could help doctors develop a test to see if other children in the family will develop the disorder, Granger said.[telegram.com]

References

Article

  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.

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Last updated: 2019-07-11 21:36