Dubowitz Syndrome

Clinical Features

Dubowitz (1965) reported 4 patients with a malformation syndrome characterized by intrauterine growth retardation, short stature, microcephaly, mild mental retardation with behavior problems, eczema, and unusual and distinctive facies. Various minor malformations, such as pilonidal dimples, submucous clefts, high-pitched voice and sparse hair, were also seen. Two of the 4 cases were full sibs with nonconsanguineous parents. An older sib of Dubowitz's original proband was probably affected but studies were not done at her death. Grosse et al. (1971) added 2 more cases. Features were intrauterine growth retardation (with primordial shortness of stature), microcephaly, variable degrees of eczema and mental retardation, and characteristic facies (blepharophimosis, micrognathia, apparent hypertelorism).

Opitz et al. (1973) concluded that eczema may be absent, stature may be normal, and intelligence may also be normal, although head circumference is always below the third percentile. They observed first-cousin parents.

Wilroy et al. (1978) reviewed 13 reported cases and 8 personally examined patients, including affected monozygotic twins and sibs. They pointed to the occurrence of hypospadias, cryptorchidism and ptosis. Orrison et al. (1980) reported 5 cases of which 2 had documented abnormalities: complete occlusion of the internal carotid artery and aberrant right subclavian artery. Parrish and Wilroy (1980) characterized the voice as hoarse as well as high-pitched. They found that intelligence varied from severe retardation to average levels. Moller and Gorlin (1985) gave a follow-up of the cases reported by Grosse et al. (1971) and stated that high-pitched, hoarse voice seems to be a constant feature. See also review of Winter (1986). Kuster and Majewski (1986) reported 5 sporadic cases and found 33 cases in the literature. The case reported by Kondo et al. (1987) demonstrates that the syndrome occurs in Orientals as well as in Caucasians.

On the basis of 21 personal observations and a review of the literature, Ilyina and Lurie (1990) pointed out that, in spite of marked microcephaly, severe mental deficiency is rare in Dubowitz syndrome and about half the patients are mentally normal. They suggested the existence of a 'new' clinical subtype that includes anorectal anomalies and premature craniosynostosis. All 3 families with this subtype were natives of a restricted area of Byelorussia called Polessie (Woodland). Lerman-Sagie et al. (1990) described 2 new manifestations: velopharyngeal insufficiency and hypoparathyroidism. The affected child had fully recovered from 'transient' congenital hypoparathyroidism but redeveloped the disorder at age 6 years. Thuret et al. (1991) reported the cases of 2 Caucasian sisters who, in addition to other features, had repeated infections and recurrent ulcerative stomatitis. They suffered from recurrent neutropenia. One had complete IgA deficiency with elevated IgM levels; the other had low values of both IgA and IgG with an increased level of IgM. An increased rate of chromosomal breakage was demonstrated in both. Thus, the disorder shares features with Fanconi anemia (227650). The frequency of malignant tumors may be increased in the Dubowitz syndrome. Bone marrow failure had previously been reported in 5 patients (Walters and Desposito, 1985; Berthold et al., 1987; Ilyina and Lurie, 1990). The lack of a basic biochemical characterization of Dubowitz syndrome makes it impossible to be completely certain of the diagnosis in these cases.

Lyonnet et al. (1992) commented on the paucity of information on the clinical features of Dubowitz syndrome in older patients. This deficiency was corrected in part by Hansen et al. (1995) who described long-term follow-up of one of the first patients to be diagnosed with Dubowitz syndrome (Grosse et al., 1971). Photographs of her in infancy and childhood were used to illustrate the publication by Grosse et al. (1971) and were reprinted in 'Smith's Recognizable Patterns of Human Malformation' (Jones, 1988).

Hansen et al. (1995) provided pictures at the age of 30 years. Microcephaly, short stature, leg length discrepancy, hyperextensible joints, spina bifida occulta, and absence of anterior cruciate ligaments were present. Her facial appearance had been modified by several plastic surgery procedures. Eczema resolved with age, with occasional flareups. Asthma, headaches, and seizures were additional medical problems. Speech delays, an unusually soft and high-pitched voice, submucous cleft palate, and velopharyngeal insufficiency were noted in childhood. Mild mental retardation was present. At the age of 30 years, the patient lived independently and worked full time in a sheltered workshop.

Tsukahara and Opitz (1996) reviewed clinical information on 141 individuals with Dubowitz syndrome, 105 reported since 1965, and 36 previously unreported. They suggested that facial anomalies are perhaps the most diagnostic of the physical signs. Microcephaly was present in 112 of the patients, blepharophimosis in 60, and ptosis in 53. They considered a prominent round tip of the nose, noted in 17 of their 34 cases, to be especially characteristic of the Dubowitz syndrome at a young age. In the total of 141 patients, normal appearance was found 15 times. Affected sibs were found in 9 families, with both sexes being affected. In 2 of 15 familial cases, the parents were consanguineous. One set of concordantly affected monozygotic twins was known, as well as a set of dizygotic twins with only 1 twin affected.

Ahmad et al. (1999) reported a girl with Dubowitz syndrome and a persistently low cholesterol level. Plasma cholesterol levels persistently ranged from 60 to 80 mg/dl (normal is more than 100 mg/dl). Other components of the cholesterol profile (e.g., low density lipoprotein and high density lipoprotein) were normal, as were the cholesterol levels in both parents. A 7-dehydrocholesterol level was normal, ruling out Smith-Lemli-Opitz syndrome (270400). Plasma sterol analysis by GC/MS was also normal. The authors suggested that Dubowitz syndrome may represent another disorder caused by an alteration in sterol synthesis or transport, or metabolism.

Al-Nemri et al. (2000) reported a newborn girl with possible Dubowitz syndrome, who also had embryonal rhabdomyosarcoma and multiple spontaneous chromosome breaks. The tumor was resected, but recurred, resulting in the infant's death at age 3 months.

Yesilkaya et al. (2008) reported a 16-year-old boy, born of consanguineous Turkish parents, with short stature, delayed psychomotor development, and dysmorphic facial features most consistent with a diagnosis of Dubowitz syndrome. Brain MRI showed an arachnoid cyst and laboratory studies showed persistently low serum lipid levels. Yesilkaya et al. (2008) noted that Ahmad et al. (1999) had also reported an association between Dubowitz syndrome and low cholesterol.

Inheritance

In the review by Opitz et al. (1973), first-cousin parents in 1 of 7 families and 2 affected sibs in at least 4 families were noted. These findings were compatible with autosomal recessive inheritance.