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2003-04-02-10 Holt-Oram syndrome © Cuillier www.thefetus.net/


Holt-Oram syndrome

Fabrice Cuillier F, MD, Broussin B,MD, Malauzat A,MD. 

Department of Obstetrics and Gynecology, Hôpital Félix Guyon, Topazes Street, 97400 Saint-Denis, Reunion Island, France. Ph : 0262 90 55 22. Fax : 0262 90 77 30.
Echographist. Expert next to the tribunal of Bordeaux. Medical Imagery Center, 120 G. Bonnac Street, 33000 Bordeaux, FRANCE.
Department of Gynecology and Obstetrics, Hospital of Perigueux, G. Pompidou street, 24000 Perigueux. FRANCE.

Definition  

The Holt Oram syndrome  is a syndrome1-2 with heart abnormalities and radial ray limb deformations3-4 with often a triphalangeal thumb5. The Holt Oram syndrome is an autosomal dominant defect with 100% penetrance. No correlation exists between the maternal clinical expression and the one of the affected offspring6-7. Real-time ultrasound with a detailed study of the fetal heart and skeleton can discover this syndrome. This report presents the ultrasonographic discovery of a fetus with Holt Oram syndrome in a non-affected family and describes another cases in literature discovered by ultrasound. 

Synonyms 

Holt Oram syndrome; Atrio-digital syndrome; Ventriculo-radial syndrome; Heart-hand syndrome.

Case report 

Ms. S., 25-year-old, gravida 3, para 1 (one child without any abnormality and one miscarriage) was sent to our unit at 22 weeks of amenorrhea for detail ultrasound scan. At 12 weeks, a single foetus with two arms was seen. At 16 weeks, the amniocentesis result was normal. The scan showed a ulnae alone with two clubbed arms on the upper limbs (Fig. 1 and 2). A tetralogy of Fallot was also suspected.

Figure N°1 :
Scan of the right forearm made at 22 weeks of gestation. The scan showed a ulna alone with clubbed arm.

 

 

Figure N°2 :
Scan of the left forearm at 24 weeks of gestation. The scan showed the ulna alone.

A second opinion was requested (Dr Broussin). The 24-week biometry was normal and a bilateral meromelia with absence of radii and hypoplastic ulnae was confirmed. The tetralogy of Fallot was confirmed. The feet were in equinus position. The rest of the exam was normal. Due to the malformations, the parents requested termination at 25 weeks of gestation.

The postmortem examination showed a foetus weighing 702 g. The radiography confirmed the absence of radii. The external examination noticed a little facial dysmorphy, a micro-retrognathism, a short neck but not widened. All the external openings were permeable. A meromelia of the upper limbs with radial angulation of the wrist was present. The thumbs were triphalangeal (Fig. 3 and 4).

Figure N°3 :
Profil of the left forearm of the foetus at 24 weeks of amenorrhea. The thumb is on the same plane as the fingers and is triphalangeal.

 

Figure N°4 :
Profile of the fetus at 24 weeks of amenorrhea. The forearm is seen with the radial ray limb deformation.

 

The macroscopic examination found dextroposed and dilated aorta with pulmonary stenosis, ventricular septal defect and right ventricle dilatation.
In fact, the fetus showed a meromelia by bilateral absence radii with a Fallot’s tetralogy, which can accompany a Holt Oram syndrome. Without any familial context, the neomutation hypothesis was probable. The parents of the child agreed with a radiologic study of the upper limbs and with a echocardiography and thus hereditary pathology was eliminated.
In 1997, the patient began a new pregnancy. At 22 weeks of gestation, the morphologic fetal scan was normal and the patient gave birth to a normal boy.

History    

Mary Holt and Samuel Oram described their syndrome in 19608-9-10 in this manner: "ASD with arrhythmia and hypoplasia of the veins and large arteries. Extra or deformed carpals, absent or hypoplastic thumb. If the thumb is present, it is spindly (like the other fingers) with three phalanx".
Later Lewis spoke about "atrio-digital syndrome", then "ventriculo-radial syndrome"11.
Two hundred cases were reported in 1990 in literature and "a genetics department in the UK near a cardiology referral center may expect to see a new family about once  every two years" 12.

Prevalence

The prevalence of the Holt Oram syndrome is estimated at 0.1:10 000 births6. Females are more commonly affected12.

Etiology 

The Holt Oram syndrome is an autosomal dominant disease, characterized by a complete penetrance but variable expression of both cardiac and skeletal defects.

Pathogenesis 

Anomaly of the cardiomelic developmental field. 50 % to 85 % of the cases of Holt Oram syndrome are caused by new mutations6, as in our case. The gene responsible for it is situated on the long arm of the chromosome 127. Mutations in two of the T-box genes (TBX5 and TBX3) on chromosome 12q24 have been shown to be responsible for the congenital anomalies associated with Holt Oram syndrome; TBX5 is only involved in anterior limb development.

Associated anomalies 

The skeletal abnormalities are asymmetric, the left side is more severely affected (69 %)8-11-13. The radii abnormalities can be unilateral and can vary to subtle abnormalities, such as clinodactyly or deformity of the carpal bones visible solely by radiographies, to severe phocomelia7-12 (10 %).
The most frequent thumb abnormalities is the
triphalangeal thumb. This thumb "hyperphalangy" looks like a forefinger. It can be spindly, bifid or absent. Sometimes a clinodactyly is present, or a syndactyly with the forefinger, an absence of the first metacarpal. The abnomalities of the thumb often integrate in a wider malformation of the radial ray anomalies with styloid agenesis, shortening or aplasia. The abnormalities of the thumb, whatever the type, are present in 84 % to 100 % of the cases2. Sometimes the thumb seems normal, but the patient is unable to oppose his thumb completely.
The second and the fifth finger can be abnormal (syndactyly, brachydactyly, little medium phalanx, clinodactyly). Deformed carpals and additional bones can exist14. According to Schwartz, these abnormalities are more specific of the Holt Oram syndrome than thumb abnormalities15.
As far as muscular abnormalities are concerned, they are consequences of secondary amyotrophy.
There isn’t any correlation between the severity of the skeletal defects and the cardiac defects16.  
The atrial septal defect-like ostium secundum is the most frequent, affecting the medium portion of the septum4.  A ventricular septal defect is present in 5 % to 20 % of the cases18. These two deformities are present in two third of the cases, but sometimes associated with another cardiac abnormalities. The cardiopathy can simply be a atrio-ventricular block of the first degree or a more complicated arrhythmia19-20. Sometimes these arrhythmia can vary in time in the same patient. When the mother carries the defective gene, her children have more serious cardiac abnormalities12.  6 % of the patients with Holt Oram syndrome have a serious cardiac deformation (responsible for 50 % of death)6.
In the initial description of the Holt Oram syndrome10, the authors described a hypoplasia peripheric vascularization. In fact, it is uncommon (11 cases since 199321).
A few other inconstant anomalies such as renal anomalies have been reported too.

Differential diagnosis   

The diagnosis of Holt Oram syndrome is easy when family history is known, but in our case, other diagnosis could be suggested, like cardio-skeletal syndromes :

  • The TAR syndrome : acronym for Thrombocytopenia with Radii Aplasia, it is revealed by clubbed hand, absence of radii, absence or hypoplastic ulna. But the thumb is constantly normal. A ASD or a Fallot’s tetralogy is present (66 %).
  • The VACTERL syndrome : is the acronym for Vertebral defect (70 %), Anal atresia (80 %), Cardial defect (53 %), Tracheo-Esophagal fistula (70 %), Radial limb defect (65 %). Three defects must be present to confirm the diagnosis21.
  • The Ventriculo-radial syndrome : associates ventricular defect and absence of radii17.
  • Fanconi anemia
  • Radial ray-choanal atresia

  
The Holt Oram syndrome can look like some chromosomic aberrations like

  • Trisomy 18
  • Trisomy 13 
  • Partial Trisomy 22 :  Smith-Fraccaro’s syndrome


Some teratogen factors can be responsible for the same abnormalities as those in Holt Oram syndrome :

  • Valproique acid
  • Ethylique alcool
  • Thalidomid13.

Sonographic findings 

The upper limbs deformities of this Holt Oram syndrome are characteristic (partial or complete absence of the radii, triphalangeal thumb). The most common cardiac abnormalities are atrial septal defect (60,3 % according to Sletten6).
The ultrasound diagnosis of this polymalformation is based on the familial context, the ultrasound discovery of a sporadic case has never been described. In fact, among the limb abnormalities (which global frequency is 0,53 %), the club hand is extremely rare (1 out of 30 000) and the sensitivity of the scan for the detection of the skeletal abnormalities and especially of extremities is lower (34 %, but only 11 % before 23 weeks of gestation), just before cardio-vascular abnormalities (35 %, and 7 % before 23 weeks of gestation)13.


In the literature, we found five case-reports of antenatal diagnosis of the Holt Oram syndrome but all within a familial context :
 
The first case-reports : were reported by Muller about two pregnancies of a woman affected by a Holt Oram syndrome22.

During her first pregnancy, the first scan at 34 weeks revealed only one bone on the forearm. The right hand had four fingers and the left three. A ventricle septal defect  was suspected. These abnormalities were confirmed by the autopsy of a premature fetus. A atrial septal defect  and a ventricle septal defect, reinforced the diagnosis of the Holt Oram syndrome.
During the second pregnancy, a scan at 14 weeks saw a deviation of the forearm towards the fetal body, without radii, and three fingers on the hands. The heart was not evaluated. At 18 weeks of gestation, a ventricle septal defect  was suspected. Due to the familial history and the severity of the fetal affection, the pregnancy was interrupted and abnormalities were confirmed by the autopsy.
The third case-report : is related by Eboué17. Suspecting a Holt Oram syndrome  after discovering a wide atrial septal defect, the description of the thumb malformation "was only possible after a long examination". Eboué seemed to have a glimpse on a triphalangeal thumb which was situated on the same plane as the fingers. 
The fourth and the fifth case-reports : are reported by Brons14.
On the first foetus, the existence of a Holt Oram syndrome was suspected at 22 weeks of gestation, when a atrio-ventricular defect and a four millimeters difference between the radii were discovered. At birth, these abnormalities was not confirmed by radiography, nevertheless the thumb looked like a forefinger. The cardiac anomaly was present.
On the second foetus, a atrial septal defect was seen at 30 weeks of gestation. Before, at 13 weeks, a scan seemed normal just as the one performed at 24 weeks. The fetus was born at 39 weeks of gestation without skeletal anomalies, but the atrial septal defect was identified by the postnatal diagnosis.


Our diagnosis of Holt Oram syndrome is exceptional due to an absence of familial context. The upper limb extremity was not very well seen at 12 weeks. It is unfortunate that an endovaginal scan was not carried out. Indeed, each of the three official scans recommended in France should show the upper limb23. However, the visibility is often good at the end of the first term, excellent at the second term and it is sometimes very difficult at the third term to detect an abnormality of the limb. This is why the limbs must be seen during the endovaginal scan at 12 or 13 weeks, or at 22 weeks of gestation. The upper limb although keeping a large freedom of movement near the body or above the head, are extremely folded near the thorax or the face when the term is advanced. Looking for the mobility of the fingers can be justified up to the end of the second term, due to seriousness of the symptom that can be reported (Club hand and hematologic syndrome; Clenched hand and trisomy 18, etc23).

As for the heart, details are discovered later at about 18 to 20 weeks. At 16 weeks, great arteries, atrias, ventricles and valves are identified, so severe congenital abnormalities can be eliminated. Nevertheless, the defect of the septum will be discovered later. In our case, the suspected cardiac abnormalities were confirmed by the postmortem examination.

Prognosis 

The Holt Oram syndrome is a very rare syndrome which can be revealed by scan, but not confirmed in utero, especially when there is non previous family history. The prognosis is linked with the seriousness of the cardiopathy and with the upper limb treatment by orthopedic teams25.

Recurrence risk  50 %.

Management

The prognosis depends on the cardiopathy and the upper limb deformity. There is no intellectual deficit.

References:

1-  Zhang K, Sun Q., Cheng T.O.- Holt-Oram syndrome in China : a collective review of 18 cases. Am Heart J 1986 ; 111 : 572-9.
2-  Fryns J.P., Bonnet D., De Smet L.- Holt-Oram Syndrome with associated postaxial and central polydactyly. Further evidence for genetic heterogeneity in the Holt-Oram Syndrome. Genetic Counseling 1996 ; 7 : 323-4.
3-  Bonnet D., Terret J., Pequignot-Viegas E., Weissenbach J., Munnich A., Lyonnet S. et Kachaner- Localisation d’un gène du syndrome atrio-digital de Holt-Oram en 12q2. Arch Mal Coeur 1995 ; 88 : 661-6.
4-  Gillet J.Y., Boog G., Dumez Y., Nisand I., Valette C.- Echographie Des Malformations Foetales, Edition Vigot, p.88- p.141- p.290- p.317.
5-  Favre R.- Principales anomalies des membres: Nosologie, apport de l’échographie dans le diagnostic et les pronostics. Gynécologie Pratique 1995 ; N°75 Supplément échographie : 16-8.
6-  Sletten L.J., Pierpont M.E.M.- Variation in severit of cardiac disease in Holt-Oram syndrome. Am J Med Gene 1996 ; 65 : 128-32.
7-  Basson C.T., Solomon S.D., Weissman B., MacRae C.A., Poznanski A.K.- Genetic heterogeneity of heart-hand syndromes. Circulation 1995 ; 91 : 1326-9.
8-  Smith A.T., Sack G.H.J., Taylor G.J.- Holt-Oram Syndrome. J Pediatr 1979 ; 95 : 538-43.

9-  Elbaum R., Royer M., Godart S.- Radial club hand and Holt-Oram syndrome. Acta Chir Belg 1995 ; 95 : 229-36.
10-  Holt M., Oram S.- Familial heart disease with skeletal malformations. Br Heart J 1960 ; 22 : 236-42.
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16- Frontera-Izquierdo P., Cabezuelo-Huerta G.- Severe Holt-Oram syndrome with pulmonary hypertension. Am Heart J 1991 ; 122 : 250-2.
17- Eboué F.- Syndrome de Holt-Oram. Soir Echo Gyn Obst 1987 ; 25 : 25-6.
18- Kumar A., L. H.S. Van Mierop, Epstein M.L.- Pathogenetic implications of muscular ventricular septal defect in Holt-Oram Syndrome. Am J Cardiol 1994 ; 73 : 993-5.
19- Basson C.T., Cowley G.S., Solomon S.D., Weissman B. et al- The clinical and genetic spectrum of the Holt-Oram syndrome (Heart-Hand syndrome). N Engl J Med 1994 ; 330 : 885-91.
20- Tucker K.J., Murphy J., Conti J.B., Curtis A.B.- Syncope and sinus arrest asociated with the upper limb-cardiovascular (Holt-Oram) Syndrome. Pacing Clin Electrophisiol 1994 ; 17 : 1678-80.
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