‘Novel’ immunodeficiency syndrome may be a previously described entity

We read with great interest the report by CM Roifman describing four males who have antibody deficiency associated with multiple epiphyseal dysplasia, growth retardation and retinal dystrophy (1). Interestingly, 2 of the patients have microcephaly, while the other two have head circumferences at the third percentile. Developmental evaluations were performed in 3 patients, all of whom have borderline to mild retardation. Two of the patients also have a form of retinal dystrophy. In 1986, a case study of two brothers, 9 and 7 years of age, with microcephaly, short stature, developmental delay, craniosynostosis (only in the older child) and immunodeficiency was reported from this Institute (2). Their parents were not related and both were in good health. Immunologic defects in the brothers included hypogammaglobulinemia and deficient leukocyte chemotaxis. These patients are now 22 and 21 years of age. They have had recurrent infections including chronic ear infections, pneumonias and urinary and G.I. tract infections. Other interesting findings not observed during the original study include skeletal changes consistent with multiple epiphyseal dysplasia and scoliosis appearing in their early teens and the autoimmune phenomena of recurring pannuculitis and erythema nodosum (3). Finally, they developed a form of retinal pathology with macular degeneration and pigmented lesions resembling retinitis pigmentosum. The older patient is more severely affected with tracheal stenosis, esophageal reflux and prolonged bleeding time. The brothers currently require gammaglobulin injections about every 3 weeks to improve their conditions. Several laboratory studies were carried out to differentiate this entity from other multiple malformation disorders with immune deficiency. Nijmegen breakage syndrome was ruled out by the absence of chromosomal rearrangements, by the insensitivity of the patients fibroblasts to X-rays (Dr Painter, San Francisco) and the absence of the common Slavic 656del5 mutation (Dr Richard Gatti, Los Angeles). Studies for ADA deficiency were also negative. There was no clinical laboratory or radiological evidence of short-limb dwarfism. Likewise, cartilage-hair hypoplasia and Lowry–Wood syndrome were eliminated on the basis of clinical and laboratory findings. In 1988, we restudied our patients at 11 and 9 years of age, respectively. Both boys had normal IgG levels but had an IgG subclass deficiency (low IgG2 and IgG4 in Case 1 and low IgG4 in Case 2). Decreased cell-mediated immunity was manifested by low in 6itro lymphocyte transformation response to tetanus toxoid (Case 1 only) and low interleukin-2 production. A chemotaxic defect was still present. Despite previous immunizations, they had low levels of pneumococcal antibodies. AFP levels were undetectable. Both parents had normal serum immunoglobulin and IgG subclass levels, except IgG4 was low in the mother. Also the mother had a normal lymphocyte transformation response to antigens and mitogens. Her electroretinography and Flash-ER studies were normal. No retinal studies were performed on the father. The possibility of an X-linked condition in these patients was considered especially after another report of a male with similar clinical findings and normal parents was published (4). Therefore, linkage analysis for the family, including the two brothers, their mother and her parents, was performed using dinucleotide repeat polymorphisms on the X chromosome. Inheritance of the same maternal alleles was detected in the brothers in the Xp21.2 to Xp22.2 region. While a more definitive gene localization was not possible, we believe that this information may assist in identification of an X-linked gene responsible for this entity by positional candidate gene strategies. Such a study of Dr Roifman’s related patients, which we believe have the same (or very similar) condition, may be of great interest. Finally, we are interested in knowing whether or not leukocyte chemotaxis studies were carried out for Dr Roifman’s patients. Sincerely,