Nijmegen-breakage syndrome

Patients generally have lower than normal birth weight and are small for gestational age. If not present from birth, microcephaly develops during the first months of life and progresses to severe microcephaly. Growth failure during the first two years of life results in height that is usually less than the 3rd centile by two years of age. The linear growth rate tends to be normal after two years of age, but patients remain small for age. As the microcephaly progresses, the facial features tend to become distinct, with sloping forehead, upslanting palpebral fissures, prominent midface, long nose, and small jaw. The ears may be large. Developmental milestones are attained at the usual time during the first year. In later infancy and early childhood, borderline delays in development and hyperactivity may be observed. Intellectual abilities tend to decline over time and most children tested after the age of seven years have mild to moderate mental retardation. The children are described as having a cheerful, shy personality with good interpersonal skills. Respiratory infections are the most common. Recurrent pneumonia and bronchitis may result in pulmonary failure and early death. Chronic diarrhea and urinary tract infections may also occur. According to Wegner et al (1999), 25 of the 70 patients (35%) reported to date have developed malignancies between the ages of one and 34 years. Twenty-two of the 25 were lymphomas, of which 19 occurred before the age of 15 years. Nine out of 19 were B-cell lymphomas; 1/19 was a T-cell lymphoma. Three patients developed solid tumors: glioma (at 12 years), rhabdomyosarcoma (at four years), medulloblastoma (at eight years). Wegner et al (1999) report a high incidence of primary ovarian failure in both prepubertal girls with NBS and adolescent and post-adolescent women with NBS, as evidenced by elevated gonadotrophin levels in both groups and primary amenorrhea and lack of secondary sexual development in the latter. Whether gonadal failure is part of the phenotype in males is not yet clear. Other findings are irregular skin pigmentation, manifested as hyperpigmented or hypopigmented irregular spots, is seen in most patients. Congenital malformations, usually observed in individual cases, include hydrocephalus, preaxial polydactyly, occipital cyst, choanal atresia, cleft lip and palate, tracheal hypoplasia, horseshoe kidney, hydronephrosis, hypospadias, anal stenosis/atresia, and congenital hip dysplasia.