The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 91, Issue Supplement 4

Radial Deficiency | July 01, 2009

Genetics of Radial Deficiencies

Esther de Graaff, PhD¹; Scott H. Kozin, MD²

¹ Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: e.degraaff@erasmusmc.nl
² Shriners Hospital for Children, 3551 North Broad Street, Philadelphia, PA 19140-4131. E-mail address: skozin@shrinenet.org

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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

The Journal of Bone and Joint Surgery, Inc.

J Bone Joint Surg Am, 2009 Jul 01;91(Supplement 4):81-86. doi: 10.2106/JBJS.I.00073

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More than 15% of the anomalies described in the London Dysmorphology Database are associated with various manifestations of radial longitudinal deficiency¹. Their etiology may be genetic, environmental, or a combination of these factors. While most of the known inherited disorders are single-gene disorders, family members carrying the same mutation often show a range of phenotypes. This indicates that other genes and/or the environment play a large role in the phenotypic variability of radial longitudinal deficiency.

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Introduction

Approximately one-third of radial longitudinal deficiencies are isolated malformations^2,3. The remaining deficiencies are considered syndromic and can be associated with other anomalies, most commonly of the heart, kidney, blood, or gastrointestinal tract. Syndromes frequently associated with radial longitudinal deficiencies include thrombocytopenia-absent radius (TAR) syndrome, the VACTERL association (vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and limb anomalies), Holt-Oram syndrome, and Fanconi anemia^2,3, which will be described in more detail in this review (Table I). There are other syndromes with related genetic mutations that will also be mentioned (Table II).

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TABLE I Disorders Associated with Radial Deficiencies

Disorder	Acronym	MIM*	Primary Inheritance Pattern
Thrombocytopenia-absent radius syndrome	TAR	274000	Autosomal recessive
Vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and limb anomalies	VACTERL	192350	Autosomal recessive/complex
VACTERL association with hydrocephalus	VACTERL-H	314390	X-linked
Holt-Oram syndrome	HOS	142900	Autosomal dominant
Fanconi anemia	FA	227650	Autosomal recessive/X-linked
Duane-radial ray syndrome	DRRS	607323	Autosomal dominant
Baller-Gerold syndrome	BGS	218600	Autosomal recessive
Rapadilino syndrome		266280
Townes-Brocks syndrome	TBS	107480	Autosomal dominant
Rothmund-Thomson syndrome	RTS	268400	Autosomal recessive

MIM = Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM).

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TABLE I Disorders Associated with Radial Deficiencies

Disorder	Acronym	MIM*	Primary Inheritance Pattern
Thrombocytopenia-absent radius syndrome	TAR	274000	Autosomal recessive
Vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and limb anomalies	VACTERL	192350	Autosomal recessive/complex
VACTERL association with hydrocephalus	VACTERL-H	314390	X-linked
Holt-Oram syndrome	HOS	142900	Autosomal dominant
Fanconi anemia	FA	227650	Autosomal recessive/X-linked
Duane-radial ray syndrome	DRRS	607323	Autosomal dominant
Baller-Gerold syndrome	BGS	218600	Autosomal recessive
Rapadilino syndrome		266280
Townes-Brocks syndrome	TBS	107480	Autosomal dominant
Rothmund-Thomson syndrome	RTS	268400	Autosomal recessive

MIM = Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM).

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TABLE II Disorders with Related Genetic Mutations

Disorder	Acronym	MIM*	Primary Inheritance Pattern
Pallister-Hall syndrome	PHS	146510	Autosomal dominant
Greig cephalopolysyndactyly	GCPS	175700	Autosomal dominant
Holoprosencephaly 3	HPE3	142945	Autosomal dominant

MIM = Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM).

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TABLE II Disorders with Related Genetic Mutations

Disorder	Acronym	MIM*	Primary Inheritance Pattern
Pallister-Hall syndrome	PHS	146510	Autosomal dominant
Greig cephalopolysyndactyly	GCPS	175700	Autosomal dominant
Holoprosencephaly 3	HPE3	142945	Autosomal dominant

MIM = Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM).

Thrombocytopenia-Absent Radius Syndrome

Thrombocytopenia-absent radius syndrome (TAR; online Mendelian Inheritance in Man [MIM] #274000⁴) is characterized by hypomegakaryocytic thrombocytopenia (reduced number of megakaryocytes, leading to a reduced number of platelets) and bilateral absence of the radii with presence of both thumbs⁵. In fact, children with TAR syndrome always have thumbs (Fig. 1). Both components of the syndrome are present at birth, although the thrombocytopenia is detected in the first week after birth in only 50% of patients and within four months in 90% of patients⁵. The thrombocytopenia is transient; infants who survive the first year can achieve relatively normal platelet counts by school age. Children with TAR can display additional disorders, ranging from cow-milk allergy to anomalies of the kidney, heart, or lower limbs; the estimated incidence of TAR is one to two cases per million live births⁶.

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Fig. 1: Radiograph of an upper limb of a child with thrombocytopenia-absent radius (TAR) syndrome. The radius is completely absent (type-4 radial deficiency) but the thumb is well developed. (Radiograph courtesy of Shriners Hospitals for Children, Northern California.)

TAR is a complex genetic disorder. Using comparative genome hybridization, Klopocki et al.⁷ recently identified a microdeletion of 1q21.1 in all thirty individuals with TAR who were tested; in 75% of the patients, this deletion was inherited from an unaffected parent. This strongly suggests that although the deletion is required, it is not sufficient for displaying the TAR phenotype. It is therefore likely that a mutation in an additional gene, the TAR modifier gene, is required. All of these different deletions encompass the same minimal region of 200 kb that harbors eleven genes⁷, none of which play an obvious role either in limb or megakaryocytic development.

VACTERL

VACTERL (MIM#192350⁸) is an acronym for a complex syndrome involving at least three of the following malformations: vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and limb anomalies⁹. This syndrome has expanded from VATER (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia) through the inclusion of cardiac malformations and more specific limb anomalies. The limb defects can involve absent or hypoplastic thumbs, syndactyly, polydactyly, and radial dysplasia. Other associations, such as hydrocephalus, can also occur with VACTERL (MIM#314390¹⁰).

Very little is known about the etiology of VACTERL. Many cases are sporadic, with no recognized teratogen. This suggests a recessive mode of inheritance in most patients, although an X-linked form has been described¹¹. A number of possible causes for VACTERL have been suggested. The first mutation published was a mitochondrial np3243 point mutation, leading to a mild deficiency of complex I respiratory chain enzyme activity¹². However, the person described in this paper displayed a phenotypic spectrum that was broader than the VACTERL spectrum and, so far, no other patient with VACTERL has been found with this mitochondrial mutation¹³. A second, recently suggested risk factor for VACTERL is preexisting maternal insulin-dependent diabetes, but too few cases have been studied to confirm this¹⁴. Finally, most convincingly, a mouse model mutated for Pcsk5 was found to resemble the VACTERL phenotype. Although several heterozygous mutations in PCSK5 (located on human chromosome 9¹⁵) were also identified in patients with VACTERL, it is unclear whether these mutations are pathogenic. However, as Pcsk5 is thought to coordinately regulate caudal Hox paralogs, in part via activation of the growth and differentiation factor 11 (Gdf11), to control anteroposterior patterning, nephrogenesis, and limb and anorectal development, it is very conceivable that mutations in this gene can lead to some of the anomalies seen in VACTERL¹⁶.

A mutation that is associated with hydrocephalus has been identified in an X-linked specific form of VACTERL. In two male patients from the same small family, a mutation was found in the FANCB gene¹¹, which is also known to be mutated in patients with Fanconi anemia (see below).

Defects in the sonic hedgehog (SHH) signaling pathway have also been considered as possible causes of VACTERL. Mouse mutants in which either Shh or its intracellular transcription factors Gli2 or Gli3 are genetically removed strongly resemble the VACTERL phenotype (for a review, see Kim et al.¹⁷). In humans with VACTERL, however, no mutation has been identified in any of these GLI genes. Moreover, mutations in genes encoding SHH lead to holoprosencephaly type 3 (HPE3, MIM#142945¹⁸), an anomaly with failure of forebrain development, and are not associated with VACTERL^19,20, whereas mutations in GLI3 genes are found in individuals with the clearly distinct phenotypes of either Pallister-Hall syndrome (PHS, MIM#146510²¹) or Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700²²)^23,24. Other possible causes of VACTERL could be mutations of target genes further downstream of SHH or very minor changes in SHH functioning. The SHH protein requires a cholesterol modification for proper functioning; cholesterol-lowering statin drugs have been considered as a potential cause of VACTERL²⁵, but this has yet to be proven.

In rats, prenatal exposure to Adriamycin (doxorubicin hydrochloride) causes a VACTERL-like association, and the Adriamycin rat model is an established animal model for VACTERL²⁶. Adriamycin is an anthracycline antibiotic, which is used in chemotherapy and can intercalate in DNA, possibly causing genomic instability. It is not known if prenatal exposure to Adriamycin causes VACTERL in humans.

Holt-Oram Syndrome

The Holt-Oram syndrome (HOS, MIM#142900²⁷) is the most common of all heart-limb syndromes, with an estimated incidence of one per 100,000 total births. Both the heart and limb phenotype vary greatly, even among family members. Substantial cardiac anomalies can be accompanied by minor skeletal malformation and vice versa. The bilateral limb phenotype mainly involves the thumb, which may be absent, hypoplastic, or triphalangeal (Figs. 2-A and 2-B). Radial deficiency and occasionally ulnar deficiency may also be seen in Holt-Oram syndrome²⁸.

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Fig. 2-A Fig. 2-B: Figs. 2-A and 2-B Holt-Oram syndrome in a mother and son with varying hand phenotypes. Fig. 2-A Photograph of the hands of the mother, showing mild bilateral hypoplastic thumbs. (Photograph courtesy of Shriners Hospital for Children, Philadelphia.) Fig. 2-B Photograph of the hands of the son, showing severe bilateral thumb hypoplasia and syndactyly of the thumb and index finger. (Photograph courtesy of Shriners Hospital for Children, Philadelphia.)

Holt-Oram syndrome is an autosomal dominant heterogeneous disorder associated with over seventy mutations in the transcription factor TBX5, a gene located on chromosome 12q24.1^29,30. These mutations include single missense mutations, deletions, and several mutations leading to the formation of a truncated protein. Most mutations appear to cause haploinsufficiency (inactivation of one copy of a gene), either by a lack of binding capacity to DNA or by the loss of interaction with a coactivator. In the normal heart-development pathway, TBX5 heterodimerizes with the transcription factor NKX2.5 in order to activate downstream targets such as atrial natriuretic factor (ANF) and connexin^31,32. The coactivator required for functioning in the limb is yet to be identified³³.

Mutations in TBX5 have been identified in only 35% of patients with Holt-Oram syndrome. In addition, not all carriers of a TBX5 mutation have the Holt-Oram syndrome phenotype³⁴, further indicating the genetic heterogeneity of this disorder. The Holt-Oram syndrome phenotype overlaps with the phenotype seen in Duane-radial ray syndrome (DRRS, MIM#607323³⁵), also called Okihiro or acro-renal-ocular syndrome. Although Duane-radial ray syndrome and Holt-Oram syndrome are both associated with cardiac defects, Duane-radial ray syndrome is also associated with an eye-muscle defect as well as possible hearing loss, kidney defects, and anal stenosis³⁶. Duane-radial ray syndrome is associated with a mutation in the transcription factor SALL4^37,38. Not surprisingly, SALL4 and TBX5 act in the same pathway in both limb and heart development³⁹. Another participant in this pathway, SALL1, is mutated in a similar syndrome, Townes-Brocks syndrome (TBS, MIM#107480⁴⁰) (characterized by radial-sided limb anomalies including thumb polydactyly and triphalangeal thumb, imperforate anus, ear malformations, and sensorineural hearing loss^41,42).

Fanconi Anemia

The main clinical manifestation of Fanconi anemia (FA, MIM#227650⁴³) is anemia of all marrow elements, which usually presents during mid-childhood. In addition to being associated with the risk of acute myelogenous leukemia, Fanconi anemia is further characterized by radial longitudinal deficiency, pigmentary changes in the skin, renal defects, and a predisposition to solid tumors of the head, neck, breast, liver, esophagus, and vulva⁴⁴. Fanconi anemia is a heterogenic autosomal or X-linked recessive disorder for which, so far, mutations have been identified in thirteen different genes: FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN. The corresponding proteins have been identified; they form two complexes that are involved in the detection of DNA damage during replication. Mutations in any of the FANC genes lead to reduced repair and increased genomic instability, as can be seen by the heightened sensitivity to DNA cross-linked agents in cells derived from individuals with Fanconi anemia⁴⁵.

Three different Fanconi anemia knockout mice models (FANCA, FANCC, and FANCD2) display many of the phenotypical aspects of Fanconi anemia, such as genomic instability and reduced fertility. However, in all three mutants, the limbs appear to be unaffected^46-48. Despite this lack of limb phenotype in these mouse models, DNA damage and limb deficiency have been linked in another mouse model, in which fetal irradiation of fetuses leads to increased DNA damage, widespread apoptosis throughout the developing limb, and consequent limb deficiency⁴⁹.

The role of DNA instability in radial deficiency is emphasized by another group of autosomal recessive malformations: Rothmund-Thomson syndrome (RTS, MIM#268400⁵⁰), Rapadilino syndrome (MIM#266280⁵¹), and Baller-Gerold syndrome (BGS, MIM#218600⁵²). Different mutations in RECQL4 have been identified in persons with these syndromes^53-55. RECQL4 belongs to the RECQ gene family of DNA helicases, which function during DNA replication and maintain genomic stability (for more information, see Seki et al.⁵⁶). All three syndromes are characterized by growth retardation, radial longitudinal deficiencies, and a predisposition to the development of osteosarcoma or lymphoma⁵⁷. Intriguingly, there is no correlation between the type or position of a mutation and the clinical manifestation, again suggesting the influence of other genes.

Conclusions

The genetics of radial longitudinal deficiencies are complex. The wide phenotypic variability, even within families with the same mutation, suggests the frequent involvement of modifier genes as well as the environment.

Several kinds of genes are now known to be associated with radial longitudinal deficiency, ranging from transcription factor genes, such as TBX5 and SALL4, to DNA repair genes, such as the Fanconi anemia complex. It is clear that mutations in genes involved in genomic stability can cause limb malformations, and it is logical that these mutations can affect the development of several organs, resulting in syndromes. In contrast, mutations in a limb-specific regulatory element, as was identified in patients with preaxial polydactyly^58,59, would restrict the phenotype to the limb.

The identification of genomic stabilizing genes presents the possibility of confirming a clinical diagnosis with a molecular one. However, molecular classification is not yet specific and accurate enough to diagnose all conditions known to be associated with gene mutations. For instance, mutations in the RECQL4 gene cause three distinct disorders⁵⁷. Furthermore, the clinical features of different syndromes overlap considerably; for example, mutations in the FANCB gene have been found both in patients with Fanconi anemia as well as in patients with X-linked VACTERL with hydrocephalus¹¹.

An accurate diagnosis is very important to families in order to determine the risk of recurrence. Although many autosomal dominant conditions, including Townes-Brocks syndrome and Duane-radial ray syndrome, consistently carry a 50% risk of occurring in offspring, the reduced penetrance of TBX5 mutations may lead to a lower recurrence risk with regard to Holt-Oram syndrome. Improved molecular testing and correlation of genotype and phenotype will help to increase the accuracy of diagnosis; in addition, prenatal molecular testing of specific aspects of developmental pathways, such as mutations in the Shh regulatory element in preaxial polydactyly, could strongly indicate that a fetus will have only the limb phenotype and not the other features of, for instance, Townes-Brocks syndrome.

Radial longitudinal deficiencies are uncommon, and most are sporadic and nonfamilial, thus limiting the number of patients who are available for genetic analysis. Recent advances in technology, such as comparative genome hybridization or single nucleotide polymorphism array analysis, help in the identification of deletions and duplications in single individuals or small families, thus enabling geneticists to identify causative mutations in smaller cohorts. Image Not Available

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Topics

phenotype ; holt-oram syndrome ; mutation ; limb ; fanconi anemia ; genetic aspects ; radial aplasia-thrombocytopenia syndrome ; vacterl association with hydrocephalus

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Esther de Graaff, Scott H. Kozin; Genetics of Radial Deficiencies. The Journal of Bone & Joint Surgery. 2009 Jul;91(Supplement_4):81-86.

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