Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 231692, 631, 67045;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq27.1 | Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency | 300123 | 3 | SOX3 | 313430 |
A number sign (#) is used with this entry because of evidence that X-linked intellectual developmental disorder with isolated growth hormone deficiency is caused by duplication in the transcription factor SOX3 (313430).
X-linked panhypopituitarism (312000) is an allelic disorder with an overlapping phenotype.
Schimke et al. (1971) described panhypopituitarism in 2 half brothers with the same mother. One of the brothers was reported to have mild mental deficiency with an IQ of 74.
Phelan et al. (1971) reported 4 cases of X-linked recessive panhypopituitary dwarfism in 3 sibships connected through females. Lagerstrom-Fermer et al. (1997) reinvestigated the family reported by Phelan et al. (1971), which included affected males with variable degrees of hypopituitarism. Some affected males had died during the first day of life and exhibited postmortem findings of hypoadrenalism, presumably due to hypopituitarism. Others had variable combinations of hypothyroidism, delayed pubertal development, and short stature due to growth hormone deficiency. All surviving patients exhibited mild to moderate mental retardation.
Hol et al. (2000) reported a family in which 2 brothers had panhypopituitarism, delayed development, and variable craniofacial dysmorphism, including hypertelorism, epicanthus, synophrys, broad nasal bridge, high-arched palate, long philtrum, cup helices, and coarse facies. One had spina bifida occulta and the other had lumbosacral myelomeningocele. One brother died at age 17 months due to aspiration; the second was alive at age 12 years and required special education services.
Intellectual Developmental Disorder with Isolated Growth Hormone Deficiency
Hamel et al. (1996) reported a family in which males in 3 generations had varying degrees of impaired intellectual development, isolated growth hormone deficiency, and infantile behavior but without other consistent phenotypic abnormalities. The pedigree was consistent with X-linked inheritance. The male patients continued to grow until well into their twenties and reached a height ranging from 135 to 159 cm. Except for one, all female carriers were mentally normal; their adult heights ranged from 159 to 168 cm.
In a family with X-linked impaired intellectual development and growth hormone deficiency, Hamel et al. (1996) found linkage to chromosome to Xq24-q27.3 (maximum lod score of 3.26 at DXS294).
By linkage analysis in the family reported by Phelan et al. (1971), Lagerstrom-Fermer et al. (1997) found linkage to markers DXS737 and DXS1187 on chromosome Xq25-q26 (peak lod score of 4.12). An apparent extra copy of the marker DXS102, observed in the region of the disease gene in affected males and heterozygous carrier females, suggested that a segment including this marker was duplicated. Lagerstrom-Fermer et al. (1997) speculated that the gene causing this disorder codes for a dosage-sensitive protein central to development of the pituitary.
In 2 brothers with panhypopituitarism, delayed development, and spina bifida, Hol et al. (2000) identified a duplication of chromosome Xq26-q27. The unaffected carrier mother and maternal grandmother also carried the duplication, which was not present in a third unaffected brother. Hol et al. (2000) hypothesized that the Xq27 breakpoint was responsible for the spina bifida and that the Xq26 breakpoint was responsible for the panhypopituitarism/delayed development, as suggested by Lagerstrom-Fermer et al. (1997). Hol et al. (2000) placed the putative gene between DXS1114 and DXS1200, corresponding to the interval defined by the duplication in their family.
Solomon et al. (2002) showed that the duplication breakpoints in the families of Lagerstrom-Fermer et al. (1997) and Hol et al. (2000) were different, leading to the conclusion that the causative gene is located within a 9-Mb duplicated region. They suggested that increased dosage rather than breakpoint disruption was responsible for the phenotype and that the gene is located in the region Xq26.1-q27.3.
Raynaud et al. (1998) reported a 3-generation family in which 3 living affected males and 5 symptomatic females had mental retardation, short stature, microcephaly, and particular facial traits, i.e., high, curved forehead, midface hypoplasia, and concave nasal bridge with nasal end of normal size. The authors mapped the disorder to Xq22-q27.1.
Intellectual Developmental Disorder and Isolated Growth Hormone Deficiency
In affected members of the family reported by Hamel et al. (1996), Laumonnier et al. (2002) identified a duplication in the SOX3 gene (313430.0001). Laumonnier et al. (2002) did not identify mutations in the SOX3 gene in the family reported by Raynaud et al. (1998), suggesting genetic heterogeneity.
Solomon et al. (2007) confirmed the duplication containing the SOX3 gene in the families with X-linked hypopituitarism and mental retardation reported by Lagerstrom-Fermer et al. (1997) and Hol et al. (2000).
Hamel, B. C. J., Smits, A. P. T., Otten, B. J., van den Helm, B., Ropers, H. H., Mariman, E. C. M. Familial X-linked mental retardation and isolated growth hormone deficiency: clinical and molecular findings. Am. J. Med. Genet. 64: 35-41, 1996. [PubMed: 8826446] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<35::AID-AJMG5>3.0.CO;2-Q]
Hol, F. A., Schepens, M. T., van Beersum, S. E. C., Redolfi, E., Affer, M., Vezzoni, P., Hamel, B. C. J., Karnes, P. S., Mariman, E. C. M., Zucchi, I. Identification and characterization of an Xq26-q27 duplication in a family with spina bifida and panhypopituitarism suggests the involvement of two distinct genes. Genomics 69: 174-181, 2000. [PubMed: 11031100] [Full Text: https://doi.org/10.1006/geno.2000.6327]
Lagerstrom-Fermer, M., Sundvall, M., Johnsen, E., Warne, G. L., Forrest, S. M., Zajac, J. D., Rickards, A., Ravine, D., Landegren, U., Pettersson, U. X-linked recessive panhypopituitarism associated with a regional duplication in Xq25-q26. Am. J. Hum. Genet. 60: 910-916, 1997. [PubMed: 9106538]
Laumonnier, F., Ronce, N., Hamel, B. C. J., Thomas, P., Lespinasse, J., Raynaud, M., Paringaux, C., van Bokhoven, H., Kalscheuer, V., Fryns, J.-P., Chelly, J., Moraine, C., Briault, S. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am. J. Hum. Genet. 71: 1450-1455, 2002. [PubMed: 12428212] [Full Text: https://doi.org/10.1086/344661]
Phelan, P. D., Connelly, J., Martin, F. I. R., Wettenhall, H. N. B. X-linked recessive hypopituitarism. Birth Defects Orig. Art. Ser. VII(6): 24-27, 1971.
Raynaud, M., Ronce, N., Ayrault, A.-D., Francannet, C., Malpuech, G., Moraine, C. X-linked mental retardation with isolated growth hormone deficiency is mapped to Xq22-Xq27.2 in one family. Am. J. Med. Genet. 76: 255-261, 1998. [PubMed: 9508246]
Schimke, R. N., Spaulding, J. J., Hollowell, J. G. X-linked congenital panhypopituitarism. Birth Defects Orig. Art. Ser. VII(6): 21-23, 1971.
Solomon, N. M., Nouri, S., Warne, G. L., Lagerstrom-Fermer, M., Forrest, S. M., Thomas, P. Q. Increased gene dosage at Xq26-q27 is associated with X-linked hypopituitarism. Genomics 79: 553-559, 2002. [PubMed: 11944988] [Full Text: https://doi.org/10.1006/geno.2002.6741]
Solomon, N. M., Ross, S. A., Forrest, S. M., Thomas, P. Q., Morgan, T., Belsky, J. L., Hol, F. A., Karnes, P. S., Hopwood, N. J., Myers, S. E., Tan, A. S., Warne, G. L. Array comparative genomic hybridisation analysis of boys with X-linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. (Letter) J. Med. Genet. 44: e75, 2007. Note: Electronic Article. [PubMed: 17400794] [Full Text: https://doi.org/10.1136/jmg.2007.049049]