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Is brachydactyly due to mutation?


I have this so called "clubbed thumbs"also known as brachydactyly.

It is of D-type.

I searched for it on internet and found that it is a dominant inherited disease.

But to my surprise,none of my family members have such thumbs.Not even my great grandfather/mother had this type of thumbs.

If it is a dominant trait then why didn't it show in any other family person. Is it that I have had any mutation in my genes?


You are correct that brachydactyly is a dominantly inherited disorder and is usually caused by mutations in the BMPR1B gene.

However, not everyone who has the mutation, will have clubbed thumbs (the phenotype). This is due to a phenomenon known aspenetranceandexpressivity.

Penetranceessentially is an all-or-none phenomenon whereby certain individuals who have a mutation express the phenotype (in this case, clubbed thumbs) and some do not express it at all.

Expressivityis when individuals who have the mutation, will express the phenotype to varying extents. For example, only one thumb may be clubbed.

I hope this helped.


Is brachydactyly due to mutation? - Biology

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The term brachydactyly encompasses a group of bone dysplasias involving the phalanges and/or metacarpal/metatarsal bones of the hands and feet. There are 5 types (A–E) and several subtypes (A1–A4 E1–E3). It has an autosomal dominant pattern of inheritance with variable penetrance. Cases with recessive inheritance are extremely rare.

Brachydactyly type C (BDC) is characterised by a shortening of the middle phalanges of the second, third and fifth finger and the first metacarpal, and may also present with ulnar deviation of the index finger, polydactyly, or a distinctive hypersegmentation of the proximal or middle phalanges of the second and third fingers. The fourth digit is least affected and usually longest. 1–3 “Angel-shaped” phalanges (Fig. 1A), while characteristic of BDC, are not pathognomonic, as they may also occur in the disorder known as angel-shaped phalango-epiphyseal dysplasia. It is possible that this disorder and BDC are part of the same clinical spectrum. 1 In BDC, this feature normalises when physeal closure of the hand bones is completed, ending as simple brachydactyly. 1 Other anomalies associated with BDC are short stature with delayed bone age, Madelung deformity, hip dysplasia, talipes valgus or equinovarus or absence of middle phalanges in the toes. 2,3

(A) Radiograph of the left hand of the proband (chronological age, 7 years bone age, 5 years), with shortening of an anomalous first metacarpal (double proximal and distal epiphyseal plates) and the middle phalanges of the second, third and fifth fingers. The second finger exhibits ulnar deviation, and the fourth finger is the least affected and longest in the left hand. The proximal epiphyses of the second and third finger are dysplastic, with a conspicuous angel-shaped middle phalanx in the second finger (inset in A). (B). Radiograph of the left hand of the proband's sister (aged 5½ years with no delay in bone age), with shortening of the middle phalanges of the second, third and fifth fingers and a normal fourth finger. In this case, the first metacarpal was normal. The most salient feature is the triangular shape of the proximal epiphysis of the second finger's proximal phalanx, similar to the brother's, and the trapezoidal shape of the phalange in the middle finder. Like her brother, her second finger exhibits ulnar deviation. (C) Radiograph of the left hand of the father of the proband, which reveals only a bony remnant of a post-axial hexadactyly that was surgically corrected in childhood.

We present the case of a boy aged 7 years with radiological features compatible with BDC referred for evaluation of short stature ( z -score, −1.8). His father had unilateral post-axial polydactyly, which was also present bilaterally in a paternal uncle. Radiographic examination of the left hand and wrist revealed a bone age that was 2 years younger than chronological age and anomalies that prompted performance of a skeletal survey. The survey detected anomalies in the hands (Fig. 1A) and subtle abnormalities in the feet (mild epiphyseal dysplasia in the proximal phalanges of some toes). The radiological evaluation of a sister aged 6 years revealed lesions in the hand similar to those of the proband, although less pronounced (Fig. 1B). A radiograph of the father's hand (Fig. 1C) only revealed a bone remnant of the post-axial hexadactyly that had been surgically corrected in childhood.

Sequencing of the GDF5 gene in the proband revealed a heterozygous point substitution in exon 2 (c.1462A>T) resulting in a premature stop codon (p.Lys488*, nonsense mutation) and a truncated protein 14 amino acids shorter than the wild protein (Fig. 2A). This mutation was also found in the father and sister of the patient, but not in the healthy mother (Fig. 2B). Fig. 2C shows the family's pedigree. This is a novel variant that is probably pathogenic and with an autosomal dominant pattern of inheritance.

Novel mutation detected in the GDF5 gene. (A) Gene sequence of exon 2 in the proband, showing a c.1462A>T mutation that results in a premature stop codon and a truncated protein (p.Lys488*) (we have indicated the normal position of the stop codon with a green square). (B) Normal sequence of the same region in the healthy mother. (C) Pedigree of the family: the father and both children, in black, have a confirmed mutation in GDF5 . The healthy mother appears in white. The grey square represents a paternal uncle with bilateral post-axial polydactyly who probably has the mutation.

Growth differentiation factor 5 (GDF5) is closely associated with bone morphogenetic proteins and belongs to the transforming growth factor β superfamily, with is involved in embryonic skeletal and joint development. 4 The GDF5 gene is a mutational hotspot for disorders associated with skeletal malformations. 5 Most homozygous or compound heterozygous mutations are associated with severe diseases: Grebe type chondrodysplasia (OMIM 200700), Hunter–Thomson type acromesomelic dysplasia (OMIM 201250) or Du Pan syndrome (OMIM 228900). On the other hand, heterozygous mutations associated to milder skeletal dysplasias: proximal symphalangism 1 B (OMIM 615298) and multiple synostosis syndrome type 2 (OMIM 610017), both associated with missense mutations with gain of function, and brachydactyly type A1 and A2, also associated to missense mutations, but with loss of function. 5 Brachydactyly type C is associated with heterozygous mutations with loss of function, although 3 cases with recessive inheritance have also been reported. 6 Most mutations associated with BDC are frameshift mutations in the prodomain part of the gene, while most mutations in the mature domain are missense mutations, with a highly variable phenotypic expression. 4

The family that we present here has a nonsense mutation in the region that codes for the active domain of the protein, resulting in the elimination of its last 14 amino acids. This is the second nonsense mutation affecting the active mature domain described in the literature. 3 The first one is a similar mutation in the amino acid immediately preceding the one mutated in the family that we describe here (p.Tyr487*/c.1461T>G), which suggests that both give rise to mutant monomers and functional haploinsufficiency of GDF5 , thus causing BDC.

This study was partially funded by projects PI13/00467 and PI13/01295, integrated in the 2013–2016 R&D&I plan of the Spanish Government and co-funded by the Deputy General-Directorate of Research Evaluation and Promotion of the Instituto de Salud Carlos III (ISCIII) , the European Regional Development Fund (ERDF) and the Centro de Investigación Biomédica en Red sobre Fisiopatología de la Obesidad y la Nutrición (Biomedical Research Networking Centre on the Physiopathology of Obesity and Nutrition [CIBERobn]), ISCIII, Madrid.


Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.

Keywords: HTNB blood platelets brachydactyly cyclic nucleotide phosphodiesterases genetics hypertension type 3.


Materials and methods

Four BDA1-affected families of diverse ethnic and regional backgrounds were studied. In all the cases, the disease was inherited as an autosomal dominant trait. Diagnosis was based on physical examination, radiographic findings when available, and family history. The study was approved by the Children's Hospital of Eastern Ontario Ethics Review Committee. After receiving informed consent, genomic DNA was extracted from peripheral venous blood or saliva samples using a QIAamp DNA blood mini-kit (Qiagen, Valencia, CA, USA) or an Oragene DNA self-collection kit (DNA Genotek, Ottawa, ON, Canada).

Sequence analysis

All three exons of IHH, including flanking splice sites and untranslated regions, were amplified by PCR and sequenced using primers and conditions described earlier. 20 The single-exon gene, NOGGIN, was amplified and sequenced as described above. All primers and optimized conditions are described in Supplementary Table 1.

Restriction digest

To detect the c.383G>A or the c.389C>A nucleotide change in the IHH gene, exon 2 was amplified by PCR and subsequently digested, according to the manufacturer's instructions, with PstI or BstEII, respectively. Products were loaded on to a 1.5% agarose gel containing ethidium bromide, electrophoresed for 40 min at 100 V, and photographed under UV light. This procedure was repeated with 200 control DNA samples for both c.383G>A and c.389C>A.

Microsatellite markers

Seven markers from Marshfield's sex-averaged genetic map were examined (D2S2250, D2S433, D2S163, D2S1242, D2S424, D2S1323, and D2S126) along with two single nucleotide polymorphisms (SNPs) located upstream of exon 1 (rs437512, and rs1960326) and 3 SNPs in exon 3 (rs3731881, rs394452, and rs3099) of IHH. Genotyping was performed as described earlier. 20


The mutational spectrum of brachydactyly type C

Molecular Medicine Unit, Institute of Child Health, London, U.K.

Department of Genetics, Baylor College of Medicine, Houston, Texas

Genetic Health Services Victoria, Victoria, Australia

Department of Paediatrics, University of Melbourne, Melbourne, Australia

Genetic Health Services Victoria, Victoria, Australia

Department of Medical Genetics, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, and Department of Pediatrics, University of California, Los Angeles, California

Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London, U.K.

Instituto de Hematologica e Immulogica, Habana, Cuba

Department of Clinical Genetics, St. Mary's Hospital, Manchester, U.K.

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland

Center for DNA Finger Printing and Diagnostics, Hyderabad, India

Center for Cellular and Molecular Biology, Hyderabad, India

Cleveland Clinic Foundation, Cleveland, Ohio

Center for Biologics Evaluation and Research, Division of Cellular and Gene Therapies, U.S. Food and Drug Administration, Bethesda, Maryland

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio

Department of Genetics, Room BRB-719, 2109 Adelbert Road, Cleveland, OH 44106.Search for more papers by this author

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

University of Illinois College of Medicine, Peoria, Illinois

Molecular Medicine Unit, Institute of Child Health, London, U.K.

Department of Genetics, Baylor College of Medicine, Houston, Texas

Genetic Health Services Victoria, Victoria, Australia

Department of Paediatrics, University of Melbourne, Melbourne, Australia

Genetic Health Services Victoria, Victoria, Australia

Department of Medical Genetics, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, and Department of Pediatrics, University of California, Los Angeles, California

Imperial College of Science, Technology, and Medicine, Hammersmith Hospital, London, U.K.

Instituto de Hematologica e Immulogica, Habana, Cuba

Department of Clinical Genetics, St. Mary's Hospital, Manchester, U.K.

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland

Center for DNA Finger Printing and Diagnostics, Hyderabad, India

Center for Cellular and Molecular Biology, Hyderabad, India

Cleveland Clinic Foundation, Cleveland, Ohio

Center for Biologics Evaluation and Research, Division of Cellular and Gene Therapies, U.S. Food and Drug Administration, Bethesda, Maryland

Department of Genetics, Case Western Reserve University, Cleveland, Ohio

Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio

Department of Genetics, Room BRB-719, 2109 Adelbert Road, Cleveland, OH 44106.Search for more papers by this author

Abstract

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5. © 2002 Wiley-Liss, Inc.


Gene responsible for hypertension, brachydactyly identified

Individuals with this altered gene have hereditary hypertension (high blood pressure) and at the same time a skeletal malformation called brachydactyly type E, which is characterized by unusually short fingers and toes. The effect on blood pressure is so serious that -- if left untreated -- it most often leads to death before age fifty. After more than 20 years of research, scientists of the Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité -- Universitätsmedizin Berlin have now identified the gene that causes this rare syndrome. In six families not related to each other they discovered different point mutations in the gene encoding phosphodiesterase-3A (PDE3A). These mutations always lead to high blood pressure and shortened bones of the extremities, particularly the metacarpal and metatarsal bones. This syndrome is the first Mendelian hypertension form (salt-resistant) not based on salt reabsorption but instead is more directly related to resistance in small blood vessels.

"In 1994, when we began with the study of this disease and examined the largest of the affected families in Turkey for the first time, modern DNA sequencing methods did not yet exist. Extensive gene databases to facilitate the search for the cause of this genetic disease were also lacking back then," said PD Dr. Sylvia Bähring, senior author of the research group's publication headed by Professor Friedrich C. Luft.

"Veritable treasure trove for genetics"

In 1996, the research group succeeded in comparing the genetic material of healthy and diseased family members in order to localize the chromosome region where this disease gene must reside. The region they detected was on a segment of chromosome 12 and was an estimated 10 million base pairs in size. "Ultimately however," said Dr. Bähring, "a 16-year-old Turkish boy helped us to pinpoint this gene. He is a veritable treasure trove for the field of genetics." He also has severe high blood pressure -- like all other test subjects he is being treated anti-hypertensive drugs -- but his hands are nearly normal. Only the metacarpal bones of his little fingers are slightly shortened.

Whole-genome sequencing of the DNA from several people with the syndrome recently enabled Dr. Philipp G. Maass, Dr. Atakan Aydin, Professor Luft, Dr. Okan Toka (formerly MDC/Charité, now the University of Erlangen), Dr. Carolin Schächterle (MDC research group Dr. Enno Klußmann) and Dr. Bähring to identify the gene and six different point mutations in a total of six families from around the world. It is the gene PDE3A, which contains the blueprint for the enzyme, phosphodiesterase 3A. The six different point mutations, which the researchers pinpointed in the PDE3A gene, lead to the exchange of a single DNA building block that is different in each family. In each case, one amino acid of the enzyme is exchanged.

One gene -- two different syndromes

But how can one mutated gene cause two quite different diseases such as hypertension and brachydactyly? The ECRC researchers also provide the explanation for this in their study. The task of the phosphodiesterase encoded by the PDE3A gene is to control the quantity of the two secondary messenger proteins present in each cell, cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate), and thus to regulate the duration of their activity.

The mutations in the gene PDE3A, however, cause the enzyme phosphodiesterase to be overexpressed. Thus, it modulates too much of the secondary messenger protein cAMP (cyclic adenosine monophosphate) into AMP (adenosine monophosphate). As a result, the cell has less cAMP at its disposal. The consequence is that, in the affected family members, the smooth muscle cells of the vascular wall of small arteries divide to a greater extent. This proliferation leads to a thickening of the vascular muscle layer, and the blood vessels narrow and stiffen, resulting in high blood pressure. Furthermore, a too low cAMP level in the vascular muscle cells also leads to increased narrowing of the blood vessels.

But what effect do the lowered cAMP levels have on the development of the bones of the extremities? The gene that elicits the skeletal malformation brachydactyly type E is PTHLH (parathyroid hormone-like hormone). In the cartilage cells, a transcription factor (CREB), activated by cAMP, binds in the control region of the gene. This factor ensures that the gene is transcribed and can affect the growth of the cartilage. If there is less cAMP in the cartilage cell, this mechanism is disturbed. This situation then leads to the shortening of the metacarpals and metatarsals, namely the fingers and toes. Thus, by varying the cellular signal transduction, one point mutation can elicit two different characteristics in one and the same person.

New perspectives on hypertension development

The researchers point out that hypertension in the families they examined is not linked to dietary salt intake. The consensus of researchers so far has been that too much salt in the diet damages the kidneys and drives blood pressure up. "We have shown in our study that for the development of the inheritable form of hypertension only the blood vessels are of significance and not directly the kidneys," said Dr. Bähring, stressing the importance of this study.

First description of the disease in 1973

In 1973, the Turkish physician, Professor Nihat Bilginturan, of the Haceteppe University in Ankara, Turkey first described the disease whose genetic cause has now been elucidated by the researchers in Berlin. Dr Bilginturan noted that in an extended family living on the coast of the Black Sea several family members had shortened fingers and toes -- the medical term for this syndrome is brachydactyly (from Greek: brachus for short and daktylos for finger). Remarkably, the affected family members also had severe high blood pressure from youth on and died at a relatively young age. Untreated, their blood pressure exceeded the normal level of 140/90 mm Hg by an average of 50 mm Hg, leading to death before the age of 50, usually due to stroke. The geneticist Professor Thomas Wienker (formerly of the MDC and the University of Bonn, now at the Max Planck Institute for Molecular Genetics, Berlin) discovered Bilginturan's publication and set the wheels of research in motion.


Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly

Background: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred.

Methods: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.

Results: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

Keywords: brachydactyly chst11 overriding-finger/toe polysyndactyly skeletal defects.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.


Contents

Brachydactyly type D is a skeletal condition which exhibits a 'partial fusion or premature closing of the epiphysis with the distal phalanx of the thumb', according to Goodman et alia (1965). [7] J.K. Breithenbecher (1923) found that distal phalanges of stub thumbs were one-half the length of full-length thumbs, while R.M. Stecher (1957) claimed that it be approximately two-thirds. The condition may either be unilateral (affecting one thumb) or bilateral (affecting both). [7]

A genetic trait, brachydactyly type D exhibits autosomal dominance and is commonly developed or inherited independently of other hereditary traits. The condition is associated with the HOXD13 gene, which is central in digital formation and growth. [6]

A 1965 scientific study in Israel found that 3.05% of Palestinians in Israel had one or two stub thumbs, compared with 1.57% among Ashkenazi as well as non-Ashkenazi Jews. [7] However, as the survey's Arab test persons were mainly recruited from a handful of large and closely related clans living in a particular village, said percentage should be 'considered with some reservation', according to Goodman et alia (1965).

Cases of stub thumbs have also been found in Eastern Nepal for Jirel ethnic individuals from their participation in various epidemiologic studies. Some studies included taking radiographs of hands and wrists to examine their skeletal structure. Of the studied sample (which included 2,130 participants 969 male and 1,161 female), 3.55% were found to have brachydactyly type D. [10]

The condition is known under numerous names. The most commonly used name is clubbed thumb, or club thumb. [8] [9] American researcher R.A. Hefner used the terms "short thumb" and "brachymegalodactylism" in 1924, [3] and "short thumb" has continued to be used in a few other studies since then, including the study that defined Rubinstein–Taybi syndrome in 1963. [1] "Stub thumb" is the common term preferred by the online database Online Mendelian Inheritance in Man [6] and was first used in a 1965 study. [7] Stub thumbs have also been called murderer's thumb (allegedly among fortune tellers), [7] bohemian thumb, Tory's thumb, and potter's thumb. [6]

The term "clubbed thumb" should not be confused with nail clubbing, which is a clinical sign associated with a number of diseases.


Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome

Mutations in ROR2 result in a spectrum of genetic disorders in humans that are classified, depending on the nature of the mutation and the clinical phenotype, as either autosomal dominant brachydactyly type B (BDB, MIM 113000) or recessive Robinow syndrome (RRS, MIM 268310). In an attempt to model BDB in mice, the mutation W749X was engineered into the mouse Ror2 gene. In contrast to the human situation, mice heterozygous for Ror2(W749FLAG) are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2(W749FLAG/W749FLAG) and a previously engineered mutant, Ror2(TMlacZ/TMlacZ), lack the P2/P3 joint. Absence of Gdf5 expression at the corresponding interzone suggests that the defect is in specification of the joint. As this phenotype is absent in mice lacking the entire Ror2 gene, it appears that specification of the P2/P3 joint is affected by ROR2 activity. Finally, Ror2(W749FLAG/W749FLAG) mice survive to adulthood and exhibit phenotypes (altered body composition, reduced male fertility) not observed in Ror2 knockout mice, presumably due to the perinatal lethality of the latter. Therefore, Ror2(W749FLAG/W749FLAG) mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse.