Dubowitz syndrome

Dubowitz syndrome is a rare genetic disorder characterized by microcephaly, growth retardation and a characteristic facial appearance (small, round, triangular shaped with a pointed, receding chin, a broad, wide-tipped nose, and wide-set eyes with drooping eyelids.) Symptoms vary among patients, but other characteristics include a soft, high pitched voice; partial webbing of fingers and toes; palate deformations; genital abnormalities; eczema; hyperactivity; preference for concrete thinking over abstract; language difficulties and aversion to crowds.(1) The pathogenesis of the disease is yet to be identified and no medical tests can definitively diagnose the disease.(2)  The main method of diagnosis is through identification of facial phenotype. Since it was first described in 1965 by English physician Victor Dubowitz, over 140 cases have been reported worldwide. A majority of cases have been reported from the United States, Germany and Russia, and it appears to affect all ethnicities and genders equally.(3)

Genetic Component
Although the exact pathology of Dubowitz syndrome is not yet known, it is almost certain that it has a genetic component. It is classified as an autosomal recessive disease, one that can be passed down through the generations. Furthermore, there is an occasional parental consanguinity. Several cases point to Dubowitz syndrome occurring in monozygotic twins, siblings as well as cousins.(4) However, although it is a recessive trait that can be expressed to cause disorder symptoms, there has been found to be a variation in the phenotypic expression.(5)  In some cases, in spite of the common symptom of microcephaly, the degree of mental retardation varies among patients. Although there is considerable evidence pointing to the genetic basis of this disorder, the symptoms that are expressed are very similar to fetal alcohol syndrome and further studies need to be done in order to determine whether this environmental agent has an affect on the expression of the genotype.(6) In addition, one of the symptoms of Dubowitz syndrome includes the breakdown of chromosomes.(7)

Growth Hormone
It has been found that Dubowitz syndrome is accompanied by a deficiency in the growth hormone.(8) This is apparent in the stunted growth of individuals with this disorder. Growth hormone is secreted by the anterior pituitary of the brain. Its main function is increasing the height of an individual during development, although it also plays a role in regulating immune function, increases calcium retention, increases muscle mass and stimulates gluconeogenesis. A deficiency in growth hormone may be caused by gene mutations, malformations of the hypothalamus or pituitary gland during development or damage to the pituitary.(9) In Dubowitz syndrome, the cause is most probably due to the gene mutations or disruption of brain structures during development. Growth hormone deficiency also has a correlation with low levels of IgG, a condition found in Dubowitz patients.(10)

Microcephaly
Microcephaly is a characteristic in which the circumference of the head is smaller than normal due to improper development of the brain. It is generally caused by genetic disorders, infections, radiation, medications or alcohol abuse during pregnancy. Defects in the growth of the cerebral cortex lead to many of the features associated with microcephaly.(11) There is no way to treat this abnormality in a way that will return the head or brain size to normal. However, there are treatment programs that are symptomatic and supportive such as physical and speech therapy and medication for seizures and hyperactivity.(12) Microcephaly has a wide range of prognoses: some patients experience very little mental retardation and can reach regular age-appropriate milestones, while others experience severe mental retardation and neuromuscular side effects.(13)

Relation to SLOS
Another lead that researchers have found in their quest for a genetic basis for Dubowitz Syndrome is in investigating Smith-Lemli-Opitz Syndrome (SLOS). Patients with SLOS and Dubowitz syndromes experience many of the same abnormalities and are therefore hypothesized to be linked. A characteristic of SLOS is a low cholesterol level and a high 7-dehydrocholesterol level. Cholesterol plays many important roles in the body: it is essential for cell membrane structure, steroid and sex hormone synthesis, and embryogenesis. Impaired cholesterol biosynthesis or transport could account for many of the symptoms of both SLOS and Dubowitz. Although only a few patients with Dubowitz syndrome have been identified as having altered cholesterol levels, the question has arisen among researchers as to whether Dubowitz shares another common feature with SLOS: a link to a defect in the cholesterol biosynthetic pathway.(16)

Due to the very low prevalence of the disease, and the wide array of symptoms associated with it, the exact biochemical pathology of the disease is still being researched. There are several studies that focus on different aspects of the disease to try to find its exact cause and expression. One study done examined the specific oral features in one patient.(14) Another study found abnormalities in the brain, such a corpus callosum dysgenesis, an under developed anterior pituitary and a brain stalk with an ectopic neurohypophysis.(15)

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