Alternative titles; symbols
SNOMEDCT: 720568003; ORPHA: 1276; DO: 0111247;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p12.2 | Hypertension and brachydactyly syndrome | 112410 | Autosomal dominant | 3 | PDE3A | 123805 |
A number sign (#) is used with this entry because of evidence that hypertension and brachydactyly syndrome (HTNB) is caused by heterozygous mutation in the PDE3A gene (123805) on chromosome 12p12.
The hypertension and brachydactyly syndrome (HTNB) is characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation, and death from stroke before age 50 years when untreated (summary by Maass et al., 2015).
Bilginturan et al. (1973) described a form of brachydactyly manifested by shortening of both phalanges and metacarpals and associated, probably as a pleiotropic effect, with hypertension. An extensive pedigree was well documented.
Schuster et al. (1996) stated that the family reported by Bilginturan et al. (1973) lived in a remote area on the northeastern Black Sea coast of Turkey. Some members were residing in Germany. Schuster et al. (1996) performed a comprehensive medical examination on 6 members (5 affected and 1 unaffected) of this Turkish family. None of them was being treated for hypertension at the time of the study. The affected individuals were not salt sensitive and the humoral responses (including renin, aldosterone, and catecholamine) to volume expansion and contraction were normal, thus resembling essential hypertension (145500) and suggesting that the renin-angiotensin-aldosterone and the sympathetic nervous systems may not be responsible for the hypertension. Schuster et al. (1996) suggested that a not yet known mechanism of blood pressure elevation was possibly involved.
Bahring et al. (1996) demonstrated loops in the posterior/inferior cerebellar artery by magnetic resonance imaging (MRI) angiography of the posterior fossa vessels in 15 patients with this syndrome. It was present bilaterally or unilaterally in all affected individuals and in none of the unaffected members of the kindred. Bahring et al. (1996) speculated that neurovascular compression resulting from the looping might be responsible for the hypertension.
Chitayat et al. (1997) reported 2 families with this disorder. All affected members of the first family had proportionate short stature, whereas the propositus and the affected relatives in the second family were only short compared to unaffected relatives. Hypertension was medically responsive in all cases. The propositus in the second family had poor compliance and a striking retinal arteriopathy.
Hattenbach et al. (1998) reported the ophthalmologic findings in all 29 affected members of the Turkish kindred originally reported by Bilginturan et al. (1973). Other than markedly elevated blood pressures and the residua of stroke in a few subjects, the apparent lack of end-organ damage was striking, including the normal-appearing fundi. Systolic blood pressures ranged from 110 to 250 mm Hg, while diastolic blood pressures ranged from 100 to 150 mm Hg in affected individuals. In all affected subjects, the fundi were only minimally altered or clinically normal. All 3 fluorescein angiograms were normal. Despite severe hypertension since childhood, the patients showed no signs of hypertensive retinopathy.
In a review of the clinical and genetic features of autosomal dominant hypertension and brachydactyly, Luft et al. (2003) noted that magnetic resonance angiographic studies in 15 hypertensive affected and 12 normotensive unaffected members of the Turkish family originally described by Bilginturan et al. (1973) demonstrated neurovascular contact in all 15 affected individuals and none of the unaffected individuals (Naraghi et al., 1997). All of the affected individuals had left-sided posterior inferior cerebellar artery or vertebral artery loops contacting the ventrolateral medulla, and 6 had bilateral neurovascular contact. Linkage analysis for the 2 traits (hypertension-brachydactyly and neurovascular contact) with chromosome 12p markers yielded a lod score of 9.2, making the odds that these 2 traits are linked to this locus greater than 1,000,000,000:1.
Schuster et al. (1996) undertook a linkage study of the family originally described by Bilginturan et al. (1973), motivated by the possibility that identification of the genetic basis of this rare monogenic form of hypertension might assist in elucidation of the multifactorial causation of essential hypertension. By linkage analysis they succeeded in localizing the responsible gene to 12p in a region defined by markers D12S364 and D12S87. (From the location of these markers the gene probably lies in the region 12p12.2-p11.2.)
In the Canadian family and the US family, neither of Turkish ancestry, described by Chitayat et al. (1997), Toka et al. (1998) found that microsatellite markers on 12p cosegregated with the phenotype, indicating that these families and the Turkish families have a defect in the same gene. Toka et al. (1998) referred to the brachydactyly as type E (113300); it was associated with short stature as well as severe hypertension.
By genomewide parametric linkage analysis, Gong et al. (2003) identified a locus for primary hypertension on chromosome 12p (HYT4; 608742) that overlaps the locus associated with severe autosomal dominant hypertension and brachydactyly.
Nagai et al. (1995) described a 5-year-old Japanese boy who had radiographic findings characteristic of ATD or EVC syndrome in association with a de novo del(12)(p11.21p12.2). He also had mild mental retardation, short stature, hypoplastic hair and skin, oligodontia, small thoracic cage, hypoplastic pelvis, and cone-shaped epiphyses of the hands. Bahring et al. (1997) restudied this Japanese boy who was found to have brachydactyly remarkably similar to that exhibited by the affected Turkish kindred with HTNB reported by Schuster et al. (1996). The Japanese child's blood pressure was 110/74 mm Hg. This value was at the upper limit of normal for age, but was lower than the blood pressures of similarly aged affected children from the Turkish family. The deleted segment in the Japanese child overlapped the segment to which the HTNB locus had been mapped. Bahring et al. (1997) reported precise mapping of the deletion in the Japanese boy, using microsatellite markers. They gave extensive descriptions of the changes in the patient of Nagai et al. (1995), pointing out the remarkable similarities to the changes in the Turkish family.
Bahring et al. (2008) performed interphase FISH in 4 families and 1 individual with hypertension and brachydactyly, including the Turkish family originally reported by Bilginturan et al. (1973) and the 2 families previously described by Chitayat et al. (1997), from the United States and Canada, respectively, and found that all of the families and the individual had rearrangements on chromosome 12p. Although the rearrangements were all slightly different, a common pattern was discernible involving an inverted area of approximately 450 kb that contains no genes but does include 5 expressed sequence tags (ESTs).
The transmission pattern of HTNB in all but 1 of the families reported by Maass et al. (2015) was consistent with autosomal dominant inheritance; the heterozygous mutation in the PDE3A gene in a single South African family occurred de novo.
In 4 families and 1 individual with hypertension and brachydactyly, including the Turkish family originally reported by Bilginturan et al. (1973) and the 2 families previously described by Chitayat et al. (1997), from the United States and Canada, respectively, Bahring et al. (2008) performed in vitro transcription/translation experiments with ESTs located within a common inverted region on chromosome 12p but found no peptide-related molecules. Quantitative RT-PCR showed that 2 products sharing 1 exon were exclusively expressed in unaffected individuals, and expression in affected individuals was completely abolished. RNA secondary prediction of that single exon resulted in a stable stem-loop structure known to be essential for microRNA processing. Bahring et al. (2008) suggested that microRNA expression in affected individuals may lead to complete downregulation of a spliced transcript.
In the Turkish family with HTNB mapping to chromosome 12p12.2-p11.2, originally reported by Bilginturan et al. (1973), Maass et al. (2015) performed whole-exome sequencing and identified a heterozygous missense mutation in the PDE3A gene (T445N; 123805.0001). The mutation segregated with disease in the family and was not found in 200 unrelated Caucasian controls or in the 1000 Genomes Project or Exome Variant Server databases. Sequencing of PDE3A in 5 additional unrelated families with HTNB, including the families reported by Chitayat et al. (1997), revealed 5 more missense mutations (123805.0002-123805.0006). All 6 mutations were clustered in exon 4, and 2 of the mutations involved the same codon. Functional analysis demonstrated that the mutations increase protein kinase A-mediated PDE3A phosphorylation, resulting in a gain of function with increased cAMP-hydrolytic activity and enhanced cell proliferation. In addition, levels of phosphorylated VASP (601703) were reduced, and levels of PTHRP (PTHLH; 168470) were dysregulated. Maass et al. (2015) suggested that these mutations cause hypertension by contributing to a general increase in peripheral vascular resistance.
Bahring, S., Kann, M., Neuenfeld, Y., Gong, M., Chitayat, D., Toka, H. R., Toka, O., Plessis, G., Maass, P., Rauch, A., Aydin, A., Luft, F. C. Inversion region for hypertension and brachydactyly on chromosome 12p features multiple splicing and noncoding RNA. Hypertension 51: 426-431, 2008. [PubMed: 18086950] [Full Text: https://doi.org/10.1161/HYPERTENSIONAHA.107.101774]
Bahring, S., Nagai, T., Toka, H. R., Nitz, I., Toka, O., Aydin, A., Muhl, A., Wienker, T. F., Schuster, H., Luft, F. C. Deletion at 12p in a Japanese child with brachydactyly overlaps the assigned locus of brachydactyly with hypertension in a Turkish family. (Letter) Am. J. Hum. Genet. 60: 732-735, 1997. [PubMed: 9042935]
Bahring, S., Schuster, H., Wienker, T. F., Haller, H., Toka, H., Toka, O., Naraghi, R., Luft, F. C. Construction of a physical map and additional phenotyping in autosomal-dominant hypertension and brachydactyly, which maps to chromosome 12. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A55 only, 1996.
Bilginturan, N., Zileli, S., Karacadag, S., Pirnar, T. Hereditary brachydactyly associated with hypertension. J. Med. Genet. 10: 253-259, 1973. [PubMed: 4774535] [Full Text: https://doi.org/10.1136/jmg.10.3.253]
Chitayat, D., Grix, A., Balfe, J. W., Abramowicz, J. S., Garza, J., Fong, C.-T., Silver, M. M., Saller, D. N., Jr., Bresnick, G. H., Giedion, A., Lachman, R. S., Rimoin, D. L. Brachydactyly-short stature-hypertension (Bilginturan) syndrome: report on two families. Am. J. Med. Genet. 73: 279-285, 1997. [PubMed: 9415685] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971219)73:3<279::aid-ajmg10>3.0.co;2-g]
Gong, M., Zhang, H., Schulz, H., Lee, A.-A., Sun, K., Bahring, S., Luft, F. C., Nurnberg, P., Reis, A., Rohde, K., Ganten, D., Hui, R., Hubner, N. Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum. Molec. Genet. 12: 1273-1277, 2003. [PubMed: 12761042] [Full Text: https://doi.org/10.1093/hmg/ddg135]
Hattenbach, L.-O., Toka, H. R., Toka, O., Schuster, H., Luft, F. C. Absence of hypertensive retinopathy in a Turkish kindred with autosomal dominant hypertension and brachydactyly. Brit. J. Ophthal. 82: 1363-1365, 1998. [PubMed: 9930264] [Full Text: https://doi.org/10.1136/bjo.82.12.1363]
Luft, G. C., Toka, O., Toka, H. R., Jordan, J., Bahring, S. Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285: R709-R714, 2003. [PubMed: 12959913] [Full Text: https://doi.org/10.1152/ajpregu.00174.2003]
Maass, P. G., Aydin, A., Luft, F. C., Schachterle, C., Weise, A., Stricker, S., Lindschau, C., Vaegler, M., Qadri, F., Toka, H. R., Schulz, H., Krawitz, P. M., and 35 others. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nature Genet. 47: 647-653, 2015. [PubMed: 25961942] [Full Text: https://doi.org/10.1038/ng.3302]
Nagai, T., Nishimura, G., Kato, R., Hasegawa, T., Ohashi, H., Fukushima, Y. Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia-like syndrome. Am. J. Med. Genet. 55: 16-18, 1995. [PubMed: 7702088] [Full Text: https://doi.org/10.1002/ajmg.1320550106]
Naraghi, R., Schuster, H., Toka, H. R., Bahring, S., Toka, O., Oztekin, O., Bilginturan, N., Knoblauch, H., Wienker, T. F., Busjahn, A., Haller, H., Fahlbusch, R., Luft, F. C. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly. Stroke 28: 1749-1754, 1997. [PubMed: 9303020] [Full Text: https://doi.org/10.1161/01.str.28.9.1749]
Schuster, H., Wienker, T. F., Bahring, S., Bilginturan, N., Toka, H. R., Neitzel, H., Jeschke, E., Toka, O., Gilbert, D., Lowe, A., Ott, J., Haller, H., Luft, F. C. Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12. Nature Genet. 13: 98-100, 1996. [PubMed: 8673114] [Full Text: https://doi.org/10.1038/ng0596-98]
Schuster, H., Wienker, T. F., Toka, H. R., Bahring, S., Jeschke, E., Toka, O., Busjahn, A., Hempel, A., Tahlhammer, C., Oelkers, W., Kunze, J., Bilginturan, N., Haller, H., Luft, F. C. Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension. Hypertension 28: 1085-1092, 1996. [PubMed: 8952601] [Full Text: https://doi.org/10.1161/01.hyp.28.6.1085]
Toka, H. R., Bahring, S., Chitayat, D., Melby, J. C., Whitehead, R., Jeschke, E., Wienker, T. F., Toka, O., Schuster, H., Luft, F. C. Families with autosomal dominant brachydactyly type E, short stature, and severe hypertension. Ann. Intern. Med. 129: 204-208, 1998. [PubMed: 9696728] [Full Text: https://doi.org/10.7326/0003-4819-129-3-199808010-00008]