Two unrelated patients with macrocephaly, seizures, and mild cerebellar signs had a dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Both also had autosomal dominant Cowden disease as evidenced by facial, oral, and acral papules. In the two families, 9 sibs demonstrated the mucocutaneous lesions, thyroid disease, breast tumors, and ovarian tumors compatible with the diagnosis of Cowden disease. Some of the sibs also showed various degrees of neurological signs such as macrocephaly, mental retardation, seizures, tremor, and dysdiadochokinesia. Magnetic resonance imaging scans of sibs of one family demonstrated megalencephaly and other mild abnormalities. The occurrence of these two rare disorders in single patients is more than a coincidence, and the clinical findings in the combined condition establishes it as a new phakomatosis.

X-linked agammaglobulinemia (XLA) is a severe humoral immunodeficiency disease of man. The inheritance of the disease is X-linked recessive. Female carriers can not be distinguished by immunologic assays. We investigated the localization of the disease gene on the X chromosome, utilizing nine polymorphic X chromosomal markers. In a single eight generation pedigree we found close linkage of the disease gene to the restriction fragment length polymorphism (RFLP) recognized by the DNA probe p19-2; the maximum lod score was 3.30 at a recombination fraction of 0.06. Addition of the lod scores for p19-2 obtained from seven other XLA pedigrees did not show the expected increase of the total score. This suggested genetic heterogeneity. We used the p19-2 marker as a reference point to search for pedigrees which had the disease gene at a different location. One pedigree provided a lod score of -3.14 at a recombination fraction of 0.06 with the p19-2 marker. We postulate that XLA is not a single genetic entity.

The gene involved in X-linked immunodeficiency with hyperimmunoglobulinemia M (XHM) was localized by the use of nine restriction fragment length polymorphic (RFLP) markers covering the entire X chromosome. Multipoint linkage analysis of RFLP data obtained in a three generation XHM pedigree indicates the Xq24-q27 area around the DXS42 RFLP locus as the most likely localization of the XHM locus.

Physicians and Surgeons, New YorkX-linked agammaglobulinemia (XLA) appears to involve a defect in human B lymphocyte differentiation which is manifested at the pre-B cell stage. The defect segregates as an X-linked recessive trait but is not a single genetic entity. IgM-producing B cell clones were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells of patients with the XLA defect linked to the DXS3 and DXS17 chromosomal loci. Individual XLA B cell clones were demonstrated to have rearrangements of the JH regions of both immunoglobulin VH region loci. The rearranged J H regions of the B cell clone ALA 19 were molecularly cloned and their nucleotide sequence was determined. Both &-associated rearrangements (designated 191 and 192) resulted from the juxtaposition of variable (VH), diversity (D) and joining (JH) segments (VHDJH rearrangements). The 191 rearrangement employed a VH segment belonging to VH subgroup 111 and a J H~ segment. The 192 rearrangement employed a VHII and a J H~ segment. The D191 and D192 segments encompassed 21 and 28 nucleotides, respectively, and showed little homology to each other or to previously reported human D sequences. Surprisingly, both VHDJH complexes had open reading frames. However, in accord with principles of allelic exclusion, only the 191 allele was detectably expressed in the total RNA of the cell. A possible mechanism for the lack of expression of the 192 allele is discussed. We conclude that the DXS3-DXS17-linked XLA defect does not preclude VH to DJH rearrangements or the expression of VH containing heavy chain molecules.

SummaryFrom a total of 160 patients with allergic bronchial asthma or chronic asthmatic bronchitis, eighteen (11.3%) patients reported being regularly exposed to pigeons. In these eighteen patients, bronchial provocation tests with pigeon faeces were performed and the precipitating antibodies (IgG) in their serum against pigeon faeces and serum were estimated. Of the eighteen patients, seven (39%) demonstrated a ‘late bronchus‐obstructive response’ to pigeon faeces. Three patients developed only an ‘isolated late response’ and in the other four patients the late response occurred as a part of the ‘dual response’. In the seven patients with the positive late bronchial response, the precipitating antibodies in their serum to pigeon faeces were positive in five (71%) and to pigeon serum in two (28%) of them. The late skin responses to pigeon faeces were positive in five (71%) patients, the blood eosinophilia increased in six (86%) of them, a slight pyrexia occurred in two (28%) and general malaise symptoms appeared in six (86%) of them. None of these patients developed changes on the chest X‐ray during the late response. The remaining eleven patients did not develop any bronchial response to pigeon faeces challenge, although in six (55%) of them the late skin responses were positive, and two (18%) had precipitating antibodies in the serum to pigeon faeces and one (9%) to pigeon serum. It is concluded that positive precipitating antibodies in the serum to pigeon faeces and serum are important parameters for detection of pigeon breeder's disease in exposed individuals, however confirmation of this diagnosis should be provided by the bronchial provocation tests.