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What Is Dubowitz Syndrome? (Part 8)

Medical problems . . .

The most common medical problems, as previously mentioned, are eczema, frequent infections (primarily viral), allergies, vomiting, and chronic diarrhea or constipation. Reviewed below are some of the more unusual and/or consequential medical problems reported in association with Dubowitz syndrome.

Skin:

A parent reported that a child was found to have a benign bony cyst of the scalp (calcified pilomatrixoma). Paradisi et al. (1994) [18] describe an Italian boy who, over a three-year period, developed scattered painless reddish-brown nodules on his face, neck and shoulder. Biopsy revealed that the nodules were composed of tissue consistent with keloids.

Kato et al. (1995) [44] describe a Japanese boy having an itchy, scaly condition on the trunk and extremities that worsened during winter. His condition had previously been diagnosed as eczema, however topical corticosteroids failed to produce improvement. A biopsy subsequently revealed skin changes consistent with ichthyosis, a skin disorder characterized by rough, dry and cracked skin and excessive keratin production. Use of a urea-containing ointment resulted in improvement. The authors, dermatologists, express the opinion that some of the skin problems described in the Dubowitz syndrome literature seemed more compatible with ichthyosis than eczema.

Hearing:

Hearing impairment was present in a number of patients resulting, in some cases, from chronic ear infections. Hearing loss as an adverse effect following the use of the antibiotic gentamycin was also reported. Tsukarhara and Opitz (1996) [11] recommend that all children with Dubowitz syndrome be examined for the presence of a submucous cleft palate (a separation of the palatal bone beneath the skin or membranes at the roof of the mouth). They write, "Submucous cleft palate is common and early detection is recommended strongly for prophylaxis [prevention] of middle ear infections."

Ocular:

Some patients have required surgical correction of drooping eyelids (ptosis) to prevent atrophy of the iris, while ptosis was corrected for cosmetic purposes in others.

Ocular abnormalities have been seen on fundoscopic examination (the back of the interior of the eye). Opitz et al. 1973 [52] describe such a finding: "Fundi showed unusually convoluted retinal vessels as well as peripheral pigmentation reminiscent of a fine-grained salt and pepper pigmentary dysplasia or degeneration." In the same article, another patient is noted to have "albinotic fundi [lacking in pigment] with increased vascular tortuosity [twisted vessels]."

Majewski et al. (1975) [51] report "prominence of the discs and unusually tortuous vessels," mentioning that five of the seven known patients had shown such an abnormality. Orrison et al. (1980) [6] observe, "A 'fan' of retina and vessels came forward from the optic nerve centrally but did not reach the posterior pole of the lens. The ocular findings were thought to represent a malformation of the retina and incomplete development and resorption of the primary vitrious posteriorly." The authors also note, "The right pupil measured 2-3 mm and responded normally to light accommodation. The left pupil was 4-5 mm in size and responded only sluggishly to light." In another patient the authors report a hypoplastic (underdeveloped) reticular (veinous) pattern of the irises.

Tsukahara and Opitz (1996) [11] cite several instances of coloboma (fissure) of the iris. Bader-Meunier et al. (1996) [29] describe two siblings with glaucoma. Kato et al. (1995) [44] describe a patient with paralysis of the right oculomotor nerve. Ilynia and Lurie (1990) [9] suggest: "It is obvious that ophthalmologic examination is necessary in every case of Dubowitz syndrome."

Vascular:

Orrison et al. (1980) [6] describe a girl who, at 3.5 years of age, suffered an episode of left arm weakness and vomiting and at a later time experienced a similar episode involving her right arm. She was subsequently admitted to the hospital with vomiting and severe headache where she later suffered apparent seizures accompanied by left-side paralysis. Tests revealed that her right internal carotid artery was completely occluded. She eventually regained partial function through intensive physical therapy.

A boy described in the same article had experienced episodic respiratory distress in addition to dysphagia (swallowing difficulty) and vomiting. Barium swallow testing revealed that his esophagus was being compressed by an aberrant subclavian artery (an artery located in the neck). The condition was surgically corrected and the child's symptoms resolved.

Cardiovascular:

Several congenital heart defects have been reported in addition to numerous heart murmurs and one instance of mitral valve prolapse.

Shuper et al. (1986) [26] report a patient with coarctation of the aorta, which is a birth defect in which the major artery (aorta) is narrowed resulting in higher blood pressure on one side and lower blood pressure on the other side of the narrowing. The condition was successfully corrected through surgery.

Ventricular septal defect (VSD), a defect in the wall separating the left and right lower chambers of the heart, has been diagnosed in several children, including a patient of Kuster and Majewski (1986) [51] whose heart catheterization revealed "a VSD, anomalies of the coronary vessels, and arteria lusuria and a right descending aorta." Kondo et al. (1987) [19] report that a VSD in their patient closed on its own without surgery.

Several children have been found to have a patent ductus arteriosus, which is an opening between the pulmonary artery and the aorta in the fetal period that normally closes at birth. Some patients required surgery while others did not.

Gastrointestinal:

Vomiting and feeding difficulties are present in a significant percentage of children with Dubowitz syndrome. Tsukahara and Opitz (1996) [11] express the opinion that the symptoms are related mostly to gastroesophageal reflux (GER) and recommend that research be carried out to discover the underlying cause.

Recently, Nowicki and Peterson (1998) [20] discovered the cause of lifelong regurgitation and symptoms of GER in at least one patient--an 18-year-old boy. The diagnosis of achalasia was made following a barium swallow study which "revealed a dilated, tortuous [twisting] esophagus with severe distal 'bird beak' narrowing" and an upper endoscopy which revealed marked dilation of the esophagus with retained food. Achalasia is very rare in children but has been reported in association with several other autosomal recessive malformation syndromes. Following treatment (pneumatic dilation), the patient, who before could swallow only puréed food, was able to tolerate a normal diet and achieve weight gain. He has been symptom-free for two years. With regard to whether or not the achalasia was responsible for the boy's lifelong history of digestive problems, Nowicki and Peterson write, "We cannot comment on when our patient developed achalasia. It was probably present for an extended period of time based on the degree of esophageal dilation." The authors recommend a stepwise approach to treating achalasia beginning with the least invasive therapy.

Diarrhea and constipation are also common in Dubowitz syndome. No explanation has been offered for the diarrhea; however, Ilynia and Lurie et al. (1990) [9] determined that congenital (present at birth) constipation in three Belarusian children was caused by anal stenosis (tightening or narrowing of the passageway). The article reports that the children were seen by a surgeon.

A child with hiatal hernia is reported by Mathieu et al. (1991) [14].

Seizures:

Seizures have occurred in association with Dubowitz syndrome. Vieluf et al. (1990) [21] describe a boy experiencing several seizures in the newborn period. Kuster and Majewski (1986) [27] report another boy who suffered grand mal seizures at the age of 2 years. The patient of Kato et al. (1995) [44] developed repeated convulsions beginning at 1.5 years which were thought to be caused by ketogenic hypoglycemia. Wilhelm and Mehes (1986) [1] describe two siblings with Dubowitz syndrome: a boy who experienced fever-related seizures at age 1, and his sister who experienced a single seizure at 10 months of age unrelated to fever. Wilroy et al. (1978) [8] report a boy who convulsed on the first day of life. In an article following-up a patient first reported in 1971, Hansen et al. (1995) [10] report that she suffered two grand mal seizures at the age of 22, and suggest her seizures may have been related to a flu-like illness and/or asthma medication.

Scoliosis:

Scoliosis (curvature of the spine) has been reported in association with Dubowitz syndrome several times--three instances in young children, and three in patients 10 years of age or older.

A 10.5-year-old girl is described by Fryns et al. [7] who give this account: "After nine years progressive idiopathic [of unknown cause] thoracolumbar scoliosis became evident. . . . A thoracolumbar scoliosis was responsible for the thoracic deformity with flat left hemithorax [flat left half of the bone structure of the chest] and a slight pectus exacavatum [sunken chest resulting from depression of the breastbone]."

Moller and Gorlin (1985) [30] provide a follow-up of a brother and sister previously described in 1971 by Gross et al. [53], and report that the eighteen-year-old sister had earlier developed a mild scoliosis and that it had been corrected.

Wilhelm and Mehes (1986) [1] describe a 5-year-old boy having mild scoliosis, and Paradisi et al. (1994) [18] present a 7-year-old patient with pectus excavatum and moderate scoliosis. The 5-year-old girl described by Antoniades et al. (1996) [24] was also said to have a "vertebral scolio-lordosis."

Soyer and McConnell (1995) [48] describe a boy having a severe and potentially life-threatening scoliosis at T5-T12, which progressed from a 25-degree to a 88-degree curvature in the space of two years from age 15 to 17. The scoliosis, described as "a left thoracic kyphoscoliosis with prominent left rib hump and elevation of the ipsilateral shoulder," led to the development of restrictive lung disease in the boy. Non-surgical treatment was attempted first with the result that the curvature was corrected to 41-degrees. Surgery was finally performed resulting in correction to 18-degrees. The authors write, "The scoliosis in this patient behaved in a fashion similar to that of neuromuscular scoliosis and thus warranted more aggressive treatment to prevent decompensation."

Malignancy, immunodeficiency, and blood abnormalities:

The first reported malignancies associated with Dubowitz syndrome involved two German sisters described by Sauer and Spelger in 1977 [40]. One of the girls developed neuroblastoma, a cancer made up of primitive cells originating from nervous system precursor cells, and her sister developed malignant lymphoma, a tumor of the lymph tissue. Sadly, both children died. The sisters also had immune system abnormalities: one had hypogammaglobulinemia (a reduced level of gamma globulin in the blood), and the other had complete IgA (the antibody, immunoglobulin A) deficiency. Sauer and Spelger suggest the immundeficiency and malignancies were interrelated.

Grobe et al. (1983) [42] report that, despite receiving chemotherapy, a German girl with Dubowitz syndrome died at age 6.75 years from acute lymphoblastic leukemia, a cancer involving proliferation of abnormal and immature lymphocytes of white blood cells.

Walters and Desposito (1985) describe an American brother and sister, both having the syndrome. The girl developed aplastic anemia (a condition in which the bone marrow ceases to produce new blood cells). Because no compatible blood donor was available, she was treated with oxymetholone, an anabolic steroid, resulting in sustained improvement. Her brother was tested as a precautionary measure, and was found to have leukopenia (reduced white blood cells), hypoplasia (a bone marrow that showed reduced cell production), and several pre-morbid signs (indicating potential development) of aplastic anemia. In their 1996 article Tsukahara and Opitz [11] report that this brother and sister are still living.

Berthold et al. (1987) [25] report a German boy who died at the age of 3 after having developed aplastic anemia 6 months earlier. (His immunoglobulins had been checked and were found to be normal.) A compatible bone marrow donor was not available, and the parents had refused to allow a transfusion on religious grounds. The child was then treated with oral oxymetholone, but unfortunately did not respond. Another 16-year-old boy developed non-Hodgkin's lymphoma, a type of cancer of the lymph tissues (Belohradsy et al. 1988 [23]), and his outcome is not known. Ilyina and Lurie (1990) [9] report a boy and girl with aplastic anemia, and their outcomes are unknown as well.

Thuret et al. (1991) [11] describe two French sisters both of whom had Dubowitz syndrome. Tests revealed hematological and bone marrow abnormalities in addition to immunoglobulin (antibody) abnormalities in both girls. One sister showed a complete deficiency of IgA, an elevated IgM, and normal IgG; the other sister had low IgA, elevated IgM, and low IgG. Chromosome breakage testing revealed an increase in both spontaneous and induced chromosomal breakage rates.

Tsukahara and Opitz (1996) [11] report a girl who had been diagnosed with pancytopenia (a marked reduction in the number of red and white blood cells and platelets) at the age of 2 years. Chromosome breakage testing of a bone marrow specimen was done twice--the first test was normal, but a later test showed extensive breakage.

Bader-Meunier et al. [29] report three affected French siblings. Blood and bone marrow studies of the first brother, done at 2 months of age, showed myelodysplasia(abnormal development of the bone marrow) resulting in a variety of blood cell abnormalities. These blood abnormalities persisted unchanged for three years, after which the child developed aplastic anemia. Later, he also developed hemolytic anemia (premature destruction of red blood cells), and subsequently died from meningitis (infection of the membranes covering the brain and spinal cord) and septicemia (blood infection) at age 3.5 years. Testing of his brother and sister revealed a variety of blood and bone marrow abnormalities, although neither child had developed aplastic anemia or malignancy as of the writing.

In their summary, Bader-Meunier et al.offer this: "These data and our report suggest that there is a subtype of Dubowitz syndrome, which includes hematological abnormalities. MDS (myelodysplasia) can be associated with several other inherited genetic disorders, including Fanconi's anemia, Bloom's syndrome, ataxia-telangiectasia, Schwachman syndrome and Recklinghausen disease. Although some phenotypic comparisons between Dubowitz syndrome and syndromes with increased spontaneous and diepoxybutane-induced chromosome breakage rates, namely Fanconi and Bloom syndromes, can be made, the cytogenetic investigations [genetic testing] exclude such diagnoses in our patients."

Chromosome breakage testing of the three French siblings revealed normal results; however, the authors point out that "the presence of a chromosome fragility [breakage] in Dubowitz syndrome is controversial since it has been found in 3 of the 7 investigated patients." The authors express the opinion that "the unexpected association of MDS [myelodysplasia] with dysmorphic features would seem to imply that a common embryological defect has occurred in several tissues." (A related article [28], Tchernia and ader-Meunier et al., Hematology and Cell Therapy (1996);38(3):325-330, can be accessed online.)

Antonaides et al. (1996) [24] describe a 5-year old Greek girl with Dubowitz syndrome having hyper-IgE syndrome, defined as a "primary immunodeficiency characterized by recurrent staphylococcal abscesses and a markedly elevated serum IgE [immunoglobulin E, an antibody] concentrations." The authors write, "It is believed that the elevated IgE levels reflect a T-cell imbalance characterized by T-cell activation and deficiency of suppressor T-cells which inhibit IgE production." The article seems to indicate that, although the child had recurrent infections primarily involving the skin and sinopulmonary tract in addition to chronic eczematoid dermatitis, she was otherwise healthy.

Although regular blood testing is recommended to monitor for the development of abnormalities, experts feel that the risk of malignancy in Dubowitz syndrome is not as high as was feared a decade or two ago when many of the malignancies were first reported.

Other:

An Israeli boy (Lerman-Sagie et al. 1990 [4]) was found to have hypoparathyroidism in the newborn period. The condition resolved with treatment, but returned again at age 6.

Two patients with the syndrome were reported to demonstrate velopharyngeal insufficiency associated with submucous cleft palate (Lerman-Sagie et al. [4] and Hansen et al. [10]).

Hirano et al. (1996) [2] describe a Japanese boy diagnosed with Dubowitz syndrome at 19 months of age. The boy apparently developed a growth hormone deficiency at some point between ages 3 and 4. The extent to which the growth hormone secretory failure influenced the boy's growth retardation is reportedly not known; however, he did experience some growth following treatment with growth hormone therapy. The authors caution that treatment with growth hormone could possibly increase the risk of leukemia in children with Dubowitz syndrome.