Beals-Hecht syndrome.

ABSTRACT: Beals-Hecht syndrome, also known as congenital contractural arachnodactyly, is caused by a defect in fibrillin as in Marfan syndrome. This syndrome is characterized by a multitude of clinical findings including arachnodactyly, narrow body habitus, scoliosis, congenital contractures, and external ear deformities. Restrictive lung disease may be associated with the severe scoliosis and thoracic cage abnormalities in this syndrome. We describe a child with Beals-Hecht syndrome and review the literature.

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BEALS-HECHT SYNDROME (Beals syndrome; congenital contractural arachnodactyly) is a rare autosomal dominant disorder characterized by arachnodactyly, narrow body habitus, scoliosis, congenital contractures, and external ear deformities. This syndrome is similar to Marfan syndrome and also results from a defect in fibrillin. We describe a 6-year-old boy with Beals-Hecht syndrome and review the literature.

CASE REPORT

A 6-year-old white boy with restrictive lung disease due to severe thoracic levoscoliosis and congenital contractural arachnodactyly (CCA) was brought to our pediatric service in respiratory distress. Peripheral oxygen saturation was 60% on room air. Five days previously, headache, fever, vomiting, and productive cough had developed. He was admitted to the pediatric intensive care unit.

The patient had been delivered by cesarean section after a full-term pregnancy. A preliminary diagnosis of Marfan syndrome was initially suspected, but CCA was diagnosed at 16 months of age. His surgical history included three palliative procedures for scoliosis with Harrington rods and spinal fusion. There are no first-degree or second-degree relatives with excessively tall stature, joint contractures, or joint dislocations. He did have a maternal great-grandfather who had had scoliosis anti whose height was 6 ft 10 inches.

Review of systems was pertinent for febrile seizures, sinus allergies, bone pain, and poor muscle tone. Clinical examination revealed a tall, thin, red-haired child with dolicocephaly, severe thoracic levoscoliosis, dolichostenomelia (narrow body habitus seen with hereditary connective tissue disorders), and arachnodactyly. He appeared alert and anxious and exhibited obvious tachypnea with both subcostal and suprasternal retractions. Initial vital signs were temperature 36.3[degrees]C (97.3[degrees]F), heart rate 113/min, respiratory rate 40/min, blood pressure 130/98 mm Hg, and peripheral oxygen saturation 93% on 3 L of oxygen via nasal cannula. Examination of the head revealed large ears with downfolded helices and crumpled-appearing anthelices bilaterally. Pulmonary examination revealed decreased breath sounds bilaterally in the bases. He had mild pectus excavatum. Cardiovascular, abdominal, and neurologic examinations were unremarkable. Examination of the extremities revealed long, gracile limbs with hyp oplastic musculature. The fingers were long and spindly with multiple contractures at the proximal interphalangeal joints, and the thumbs were adducted (Fig 1). The lower extremities were medially rotated, and the feet and toes were long and narrow, with crossing of the second toe over the great toe.

Initial laboratory evaluation, including complete blood cell count with differential and Mycoplasma IgM antibody, was normal, Sputum Gram stain, cell count, and culture showed normal respiratory flora.

Chest radiograph revealed patchy opacities in both lower lung fields and mild enlargement of the cardiac silhouette. Severe scoliosis was also apparent (Fig 2). Computed tomography of the chest showed an opacity in the right medial lung base consistent with pneumonia, atelectasis in the inferior lingula and medial left lower lobe, and diffuse opacities throughout the lungs suggestive of interstitial or peribronchial edema. An echocardiogram revealed a mildly dilated right atrium and right ventricle, but an otherwise structurally and functionally normal heart. Ejection fraction was 69%.

The patient was given ceftriaxone, nebulized albuterol, furosemide, and oxygen. By the fifth hospital day, he maintained a peripheral oxygen saturation greater than 92% on room air. Antimicrobial therapy was changed to cefzil. The patient's condition continued to improve, and he was discharged home on the seventh hospital day.

DISCUSSION

Congenital contractural arachnodactyly is an extremely rare autosomal dominant connective tissue disorder that is frequently manifested in the musculoskeletal system and less often in the cardiovascular and ocular systems. Approximately 40 families and more than 120 affected members have been reported. (1) Beals and Hecht (2) first differentiated CCA from Marfan syndrome in 1971. Both of these diseases result from defects in the large glycoprotein (350 kd) fibrillin, one of the structural components of the elastin associated microfibrils. (2,3)

Clinical manifestations common to both CCA and Marfan syndrome include tall stature, dolichostenomelia, arachnodactyly, progressive kyphosis/scoliosis, and pectus excavatum or carinatum. (4) Individuals affected with CCA are usually the product of a normal pregnancy but are frequently born by breech delivery. (1) Other phenotypic features include congenital joint contractures and abnormal "crumpled" pinnae. (5) The majority of patients live a normal life span, though cases of severe lethal CCA have been reported?. (5-8) Infants with lethal CCA can have cardiac anomalies. Those reported include atrial and/or ventricular septal defects, mitral insufficiency, interrupted aortic arch, and patent ductus arteriosus. Severe restrictive lung disease is the result of the scoliosis and thoracic cage abnormality. (5-8)

Two independent studies linked Marfan syndrome to defects in the fibrillin-1 (FBN1) gene, mapped to chromosome 15q15-21. (9,10) Genetic linkage studies conducted by Lee et a1 (9) revealed that CCA is caused by a defect in the fibrillin-2 (FBN2) gene, mapped to chromosome 5q23-31. Fibrillin-2 is homologous to the FBN1 gene at both the nucleotide and amino acid levels; however, the tissue distribution and temporal expression of FBN2 are distinct from those of FBN1. (11,12) Documented abnormalities in the FBN2 gene are diverse. Two missense mutations in fibroblasts derived from two isolated individuals with CCA have been reported. (13) Wang et al (5) reported a splicing defect in exon 34 of FBN2 in an affected mother and her child. Putnam et al (14) described somatic mosaicism of an FBN2 genomic mutation in the father of two siblings affected with CCA. A branch point mutation associated with the in-frame skipping of exon 31 has also been cited. (15) Interstitial 5q deletion involving the region q23q31 is a rare cause of CCA, with six independent cases reported to date. (16) Although many of the molecular mechanisms responsible for the disorder have been identified, the clinical variability in phenotypic expression remains an enigma. Preferential expression of the mutated FBN2 allele has been reported by Putnam et al, (14) who speculated that the clinical expression of the disease may be influenced by the amount of expression from the normal allele. Furthermore, the possibility of maternal imprinting of chromosome 5q has been proposed. (14,16) Further research is needed to elucidate the exact mechanisms responsible for the diverse phenotypic variability seen in this disorder.

The differential diagnosis of CCA includes Marfan syndrome, Achard syndrome, homocystinuria, Stickler syndrome, osteogenesis imperfecta, and distal arthrogryposis. (2,6,17-20) Beals and Hecht (2) presented the defining characteristics and separation of the first three conditions from CCA.

It is of interest that this patient was hospitalized for the second time because of severe respiratory distress. The chest wall is an integral part of the ventilatory pump. Diseases of the bony thoracic cage, such as scoliosis, share common pathophysiologic events, including alveoloar hypoventilation, changes in chest wall compliance, variable lung compression, ventilation-perfusion mismatch, pulmonary hypertension, and cor pulmonale. Patients with restrictive lung disease due to severe thoracic scoliosis, which is common in CCA, may have recurrent episodes of respiratory distress, pneumonia, and early signs of right-sided heart failure.

Congenital contractural arachnodactyly is a rare autosomal dominant connective tissue disorder with variable clinical expression. Recent advances in molecular genetics have been instrumental in differentiating this disorder from Marfan syndrome and in resolving the diverse mechanisms responsible for the clinical manifestations of this disease. Future studies will likely elucidate the basis of the variable phenotypic expression present in individuals with CCA. The cardiovascular complications seen in Marfan syndrome, including dilatation (with or without dissecting aneurysm) of the ascending aorta, abdominal aorta, or pulmonary artery and mitral valve prolapse are only rarely seen in CCA, and therefore confer a more favorable prognosis for those afflicted with CCA. (4) However, cardiovascular and pulmonary complications due to the scoliosis so common in patients with CCA may significantly alter their long-term morbidity and mortality. Further research is necessary to determine the future ramifications severe scoliosis will have on this patient and others with this disfiguring disease.

CONCLUSION

Beals-Hecht syndrome (Beals syndrome) is a rare autosomal dominant disorder manifested by arachnodactyly, narrow body habitus, scoliosis, congenital contractures, and external ear deformities. It shares features of Marfan syndrome and results from a defect in fibrillin. Restrictive lung disease may occur from the associated severe scoliosis and thoracic cage abnormalities. Although rare, this syndrome should be considered within the differential diagnosis of children with similar clinical presentation.

References

(1.) Viljoen D: Congenital contractural arachnodactyly (Beals syndrome). J Med Genet 1994; 31:640-643

(2.) Beals RK, Hecht F: congenital contractural arachnodactyly. a heritable disorder of connective tissue. J Bone Joint Surg Am 1971; 53:887-903

(3.) Tsipouras P, Del Mastro R, Sarfarazi M, et al: Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyle to the fibrilling genes on chromosomes 15 and 5. N Engl J Med 1992; 326:905-909

(4.) Sotos JF: Overgrowth. Clin Pediatr 1997; 36:91-104

(5.) Wang M, Clericuzio CL, Godfrey M: Familial occurrence of typical and severe lethal congenital contractural arachnodactyly caused by missplicing of exon 34 of fibrillin-2. Am J Hum Genet 1996;59:1027-1034

(6.) Lipson EH, Viseskul C, Herrmann J: The clinical spectrum of congenital contractural arachnodactyly: a case with congenital heart disease. Z Kinderheilk 1974; 118:1-8

(7.) Currarino G, Friedman JM: A severe form of congenital contractural arachnodactyly in two newborn infants. Am J Med Genet 1986; 25:763-773

(8.) Macnab AJ, D'Orsogna L, Cole DEC, et al: Cardiac anomalies complicating congenital contractural arachnodactyly. Arch Dis Child 1991; 66:1143-1146

(9.) Lee B, Godfrey M, Vitale E, et al: Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991; 352:330-334

(10.) Dietz HC, Cutting GR, Pyeritz RE, et al: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352:337-339

(11.) Mariencheck MC, Davis EC, Zhang H, et al: Fibrillin-I and fibrillin-2 show temporal and tissue-specific expression in developing elastic tissues. Connect Tissue Res 1995; 31:87-97

(12.) Zhang H, Hu W. Ramirez F: Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J cell Biol 1995; 129:1165-1176

(13.) Putnam EA, Zhang H, Ramirez F, et al: Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 1995; 11:456-458

(14.) Putnam EA, Park ES, Aalfs CM, et al: Parental somatic and germ-line mosaicism for a FBN2 mutation and analysis of FBN2 transcript levels in dermal fibroblasts. Am J Hum Genet 1997; 60:818-827

(15.) Maslen C, Babcock D, Raghunath M, et al: A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly. Am J Hum Genet 1997; 60:1389-1398

(16.) Courtens W, Tjalma W, Messiaen L, et al: Prenatal diagnosis of a constitutional interstitial deletion of chromosome 5 (q15q31.1) presenting with features of congenital contractural arachnodactyly. Am J Med Genet 1998; 77:188-197

(17.) Parish JG: Skeletal hand charts in inherited connective tissue disease. J Med Genet 1967; 4:227-238

(18.) Beals RK Homocystinuria. a report of two cases and review of the Literature. J Bone Joint Surg Am 1969; 51:1564-1572

(19.) Shoenfeld Y, Fried A, Ehrenfeld NE: Osteogenesis imperfecta. review of the literature with presentation of 29 cases. Am J Dis Child 1975; 129:679-687

(20.) Hall JG, Reed SD, Green G: The distal arthrogryposes: delineation of new entities, review and nosologic discussion. Am J Med Genet 1982; 11:185-239

RELATED ARTICLE: KEY POINTS

* Beals-Hecht syndrome is an extremely rare, autosomal dominant connective tissue disorder characterized by arachnodactyly, narrow body habitus, scoliosis, congenital contractures, and external ear deformities.

* This disease results from a defect in the large glycoprotein fibrillin.

* The majority of patients live a normal life span; however, severe lethal cases have been reported.

* The cardiovascular complications seen in Marfan syndrome are only rarely seen and thus confer a more favorable prognosis for those afflicted with Beals-Hecht syndrome.

* Restrictive lung disease may occur from the associated severe scoliosis and thoracic cage abnormalities.

From the Departments of Pediatrics and Family Practice, Mercer University School of Medicine, Medical Center of Central Georgia, Macon.

Reprint requests to Joshua E. Lane, MD, Mercer University School of Medicine, Medical Center of Central Georgia, 777 Hemlock St Hospital Box 162, Macon, GA 31208.