Atypical clinical picture of the Nijmegen breakage syndrome associated with developmental abnormalities of the brain.

EDITOR—Nijmegen breakage syndrome (NBS) (OMIM 251260) is a rare autosomal recessive condition. The major manifestations include microcephaly, a distinct facial appearance, growth retardation, recurring infections owing to combined immunodeficiency, spontaneous chromosomal instability (with characteristic rearrangements of chromosomes 7 and 14), hypersensitivity to ionising radiation, and a very high predisposition to lymphoid malignancy. The immunological, cytogenetic, and cell biological findings are very similar to those in ataxia telangiectasia (AT); however, NBS patients lack the neurocutaneous manifestations of AT, as well as a raised serum á-fetoprotein (AFP). Recently, the gene mutated in NBS has been cloned. The NBS1 gene is located on chromosome 8q21 and encodes a protein called nibrin, a member of the hRad50/hMre11 protein complex involved in DNA double strand break processing. 5 NBS is quite a rare disease with about 80 patients ascertained world wide, including 50 Polish. The vast majority of NBS patients are of Slavic origin and carry a common founder mutation 657del5 in exon 6. We report on a Polish patient with Nijmegen breakage syndrome presenting an atypical clinical picture with the absence of microcephaly and the presence of a congenital heart defect and preaxial polydactyly. To the best of our knowledge, no NBS patient without microcephaly or with congenital cardiac disease has ever been reported and preaxial polydactyly has been observed in only two other cases. The proband, a girl, was born at term by spontaneous vertex delivery after an uneventful pregnancy. Birth weight was 3500 g, length 55 cm, occipitofrontal circumference (OFC) 35.5 cm, and chest circumference 33 cm, all above the 50th centile. Apgar score was 9 at one minute. Clinical investigation at birth showed preaxial polydactyly of the right hand, which has been surgically corrected. No other malformations were noted at that time. She was the first child of healthy, unrelated parents. At her birth the mother and the father were 24 and 25 years old, respectively. In a following pregnancy, a healthy son was born. Besides a slight delay in beginning to walk independently, at the age of 18 months, the patient reached other early developmental milestones at the normal time. She received all appropriate vaccinations, including live polio, without incident. After the age of 2 years, she experienced several episodes of upper and lower respiratory tract infections, as well as otitis media, but admission to hospital has never been required. The patient was referred to the cardiology department for evaluation of a heart murmur. Patent ductus arteriosus (PDA) was detected and surgically closed at the age of 3 years. At the age of 5 years, she was admitted for evaluation of developmental delay. Metabolic screening including thyroid status was normal. On physical examination at the age of 5.75 years, several dysmorphic features were noted (fig 1A, B) including hypertelorism, epicanthic folds and ptosis of the right eyelid, a short and slightly upturned nose with a high and broad root, an elongated, flat, and prominent philtrum, and a small chin. The ears and hair were normal. Highly placed thumbs, with thickness of the right one, bilateral 5th finger clinodactyly, and partial syndactyly of the 2nd/3rd toes were found. Two naevi flammei and hirsutism in the lumbar area were present. Her measurements at this time were as follows: height 112.5 cm (∼25th centile), weight 17.9 kg (∼25th centile), and OFC 51 cm (∼50th centile), with cranial width less than length (dolichocephaly). A retrospective analysis of her growth parameters showed that her height and weight had usually followed the 50th-25th centile (fig 2A, B); her OFC was constantly around the 50th centile (fig 2C), although the anterior fontanelle was small from birth and closed at the age of 8 months. Her intellectual development assessed at the age of 4 years with the Terman-Merrill test indicated borderline intelligence (IQ=76). Ocular examination showed no abnormalities apart from strabismus. A very detailed neurological evaluation also showed no pathological signs. A first assessment of humoral immunity, at the age of 6 years, showed a low serum IgA level (0.06 g/l) and slightly decreased level of IgM (0.55 g/l), while a normal concentration of total IgG (5.49 g/l) “masked” deficiency of IgG2 (0.53 g/l) and IgG4 (0.019 g/l). Serum AFP level and blood lymphocyte count were within the normal limits. Lymphocyte subpopulation analysis showed a decreased T cell population (CD3+) because of helper cells (CD4+) deficiency (8%, normal value 40-60%), in particular of virgin helper cells (1.2%). Suppressor T cells (CD8+) were within the normal range (26%) and NK cells were increased (34.3%, normal value 5-10%). T cell response to PHA stimulation was very poor. Three attempts to perform chromosome analysis from PHA stimulated lymphocytes failed. In a one year interval metaphases from two successful cultures were analysed by standard harvesting and GTG banding. From the first culture, 11 of 20 mitoses showed a normal female karyotype 46,XX, eight cells exhibited unique aneuploidies, and one cell carried a translocation (7;14). In the second successful culture, only 14 mitoses could be analysed, including four incomplete metaphases. In two metaphases, an inv(7) and an add(7q) were each detected once. Summarising the data of the two investigations, in three of 34 (∼9%) analysed cells rearrangements of chromosome 7 and/or 14 could be Figure 1 (A, B) The patient aged 6 years. Electronic letter 1 of 5