Alternative titles; symbols
SNOMEDCT: 234533006; ORPHA: 231692, 631, 632; DO: 0060875;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.1 | Isolated growth hormone deficiency, type III, with agammaglobulinemia | 307200 | X-linked recessive | 3 | BTK | 300300 |
A number sign (#) is used with this entry because of evidence that isolated growth hormone deficiency type III with agammaglobulinemia (IGHD3) is caused by mutation in the BTK gene (300300) on Xq22.
IGHD3 is characterized by agammaglobulinemia and markedly reduced numbers of B cells, short stature, delayed bone age, and good response to treatment with growth hormone (summary by Conley et al., 1991).
For general phenotypic information and a discussion of genetic heterogeneity of IGHD, see 262400.
Fleisher et al. (1980) described a kindred in which 2 brothers and 2 sons of their oldest sister had hypogammaglobulinemia deficiency. Recurrent sinopulmonary infections were a prominent feature in 2 patients. Short stature, retarded bone age, and delayed onset of puberty were other features. The immunodeficiency was characterized by absent specific antibody production in vivo and impaired immunoglobulin production in vitro. In 3 of the 4 affected persons, there was marked deficiency of all immunoglobulin isotypes; in 1, IgM and IgA levels were normal although B cells were diminished in number. Three of the 4 patients lacked circulating B lymphocytes, even though tonsils were present in these patients. All 4 had deficient growth hormone responses to insulin and arginine or levodopa. Coexistence of growth hormone deficiency and immunodeficiency is found in 2 mouse mutants: the Snell-Bagg mouse and the Ames dwarf mouse. The patient who did have circulating B lymphocytes had been treated with growth hormone.
Monafo et al. (1991) described this syndrome in a 13-year-old boy. An earlier born agammaglobulinemic brother, who died at 6 years of age, was below the third percentile for height.
Conley et al. (1989, 1991) studied 2 unrelated families with this disorder. G-banded karyotypes and flow cytometric analysis of metaphase chromosomes gave no indication of deletion. Studies of X inactivation showed that the mothers of the affected boys from both families exhibited selective use of a single X chromosome as the active X chromosome in B cells but not in T cells. This pattern is the same as that seen in obligate carriers of typical X-linked agammaglobulinemia (XLA; 300300). Linkage analysis demonstrated the most likely location of the gene (or genes) to be the midportion of Xq between DXS3 and DXS94. This segment includes the gene for XLA. The findings were considered consistent with this combination of XLA and growth hormone deficiency being a contiguous gene syndrome due to deletion or its being an allelic variant of the gene for typical XLA.
Sitz et al. (1990) described a family in which 3 males in 2 generations had the combination of X-linked hypogammaglobulinemia and isolated growth hormone deficiency. The first case in the family was a boy who died at the age of 7 years of staphylococcal septicemia and had a height of 118 cm (25th percentile) at autopsy and his only brother who also had hypogammaglobulinemia which was treated with immune globulin. Height growth velocity did not decrease until age 10 years. Growth hormone deficiency was documented by a levodopa insulin stimulation test at the age of 15 years. At age 17 his height was more than 2 standard deviations below the mean and he was in Tanner stage II of sexual development. The only son of a sister of these 2 boys was found to have hypogammaglobulinemia and a partial growth hormone deficiency.
Duriez et al. (1994) presented evidence suggesting that the syndrome combining X-linked agammaglobulinemia and isolated growth hormone deficiency is caused by mutation in the BTK gene. The BTK gene was analyzed in a sporadic case by RT-PCR analysis of BTK transcripts, sequencing of cDNA and genomic DNA, and in vitro splicing assays. They found an intronic point mutation, 1882+5G-A (300300.0004), leading to skipping of an exon located in the tyrosine kinase domain. The exon skipping event resulted in a frameshift leading to a premature stop codon 14 amino acids downstream and in the loss of the last 61 residues of the carboxy-terminal end of the protein.
In 2 patients with growth hormone deficiency and agammaglobulinemia (patients 14 and 19), previously reported by Conley et al. (1991), Conley et al. (1994) identified mutations in the BTK gene, Y375X (300300.0030) and L542P (300300.0040), respectively.
Conley, M. E., Burks, A. W., Herrod, H. G., Puck, J. M. Molecular analysis of X-linked agammaglobulinemia with growth hormone deficiency. J. Pediat. 119: 392-397, 1991. [PubMed: 1880652] [Full Text: https://doi.org/10.1016/s0022-3476(05)82051-7]
Conley, M. E., Burks, A. W., Stewart, C. C., Puck, J. M. The relationship between typical X-linked agammaglobulinemia (XLA) and XLA with isolated growth hormone deficiency. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A181 only, 1989.
Conley, M. E., Fitch-Hilgenberg, M. E., Cleveland, J. L., Parolini, O., Rohrer, J. Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. Hum. Molec. Genet. 3: 1751-1756, 1994. [PubMed: 7849697] [Full Text: https://doi.org/10.1093/hmg/3.10.1751]
Duriez, B., Duquesnoy, P., Dastot, F., Bougneres, P., Amselem, S., Goossens, M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 346: 165-170, 1994. [PubMed: 8013627] [Full Text: https://doi.org/10.1016/0014-5793(94)00457-9]
Fleisher, T. A., White, R. M., Broder, S., Nissley, S. P., Blaese, R. M., Mulvihill, J. J., Olive, G., Waldmann, T. A. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. New Eng. J. Med. 302: 1429-1434, 1980. [PubMed: 7189577] [Full Text: https://doi.org/10.1056/NEJM198006263022601]
Monafo, V., Maghnie, M., Terracciano, L., Valtorta, A., Massa, M., Severi, F. X-linked agammaglobulinemia and isolated growth hormone deficiency. Acta Paediat. Scand. 80: 563-566, 1991. [PubMed: 1872183] [Full Text: https://doi.org/10.1111/j.1651-2227.1991.tb11907.x]
Sitz, K. V., Burks, A. W., Williams, L. W., Kemp, S. F., Steele, R. W. Confirmation of X-linked hypogammaglobulinemia with isolated growth hormone deficiency as a disease entity. J. Pediat. 116: 292-294, 1990. [PubMed: 2299506] [Full Text: https://doi.org/10.1016/s0022-3476(05)82896-3]