Radiological features in Brachmann-de Lange syndrome

American Journal of Medical Genetics 47:1006-1013 (1993)

Radiological Features in Brachmann-de Lange Syndrome Stephen R. Braddock, Ralph S. Lachman, Cathy Charman Stoppenhagen, John C. Carey, Maggie Ireland, John B. Moeschler, Christopher Cunniff, and John M. Graham, Jr. Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Medical Genetics Birth Defects Center, Division of Clinical Genetics and Dysmorphology, Cedars-Sinai Medical Center, Los Angeles, California (S.R.B., R.S.L., C.C.S., J.M.G.),Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah (S.R.B., J.C.C.),Division of Clinical Genetics, University of Newcastle Upon Tyme, United Kingdom ( M I . ) , Clinical Genetics and Child Development Center, Department of Maternal and Child Health, Dartmouth Medical School, Hanover, New Hampshire (J.B.M., J.M.G.), and Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Arkansas (C.C.) Brachmann-de Lange syndrome (BDLS) is a well-delineated disorder consisting variably of pre- and postnatal growth deficiency, microbrachycephaly,characteristic face, hypertrichosis, visceral anomalies, and limb defects consisting primarily of variable limb reduction defects, micromelia, and elbow abnormalities. The course is usually marked by initial hypertonicity, low-pitched weak cry, feeding problems, and behavioral problems with marked mental deficiency. In classical cases there is rarely any difficulty in making the diagnosis, but for mildly affected cases, it may be difficult to feel secure about the diagnosis. In an effort to increase the precision of diagnosis for mildly affected cases, we reviewed roentgenograms in 21 cases of Brachmann-de Lange syndrome, as well as previously published descriptions of the radiological manifestations.Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. These manifestations included digital abnormalities, which ranged from acheiria to oligodactyly, hypoplasia of the thumb and f i s t metacarpal, clinodactyly of the fifth finger, or ectrodactyly. Long bone abnormalities included ulnar aihypoplasia, dysplasia of the radial head, or fusion of the elbow. When there was a single forearm bone, there was often fusion at the elbow and oligodactyly, which made it difficult to determine whether the radius or ulna was absent. Other radio-

logic manifestations included 13ribs with precocious sternal fusion, and micrognathia. W e suggest that these radiologic manifestations could increase diagnostic precision in mildly affected cases. o 1993 Wiley-Liss, Inc.

KEY WORDS Brachmann-de Lange syndrome, radiology, mental retardation

INTRODUCTION In 1933, when Cornelia de Lange described 2 Dutch children with a syndrome that included: small nose with upturned nostrils, thin downturned mouth, synophrys, long curly eyelashes, short stature, limb malformations, and mental retardation, she had no idea that Brachmann had described a similar case in 1916. It took about 30 years before the syndrome was even printed in English [Ptacek et al., 19631. However, during the past 30 years, many children with this diagnosis have been recognized Hawley et al. (1985). The classical phenotype has been well delineated and most diagnoses present no difficulty. There has also been increased reporting of patients with a mild phenotype appearance, some of whom are parents of affected offspring [Robinson et al., 1985; Greenberg and Robinson, 19891. In an effort to increase our diagnostic precision, we have reviewed the radiological manifestations of 21 cases of Brachmann-de Lange syndrome (BDLS) with variable involvement.

CLINICAL REPORTS Patient 1: R.H. (Classic Phenotype) This was the second child to a 26-year-old mother and Received for publication November 1, 1991; revision received 32-year-old father. Pregnancy was full term and noteMay 21, 1993. Address reprint requests to John M. Graham, Jr., M.D., Sc.D., worthy only for her third trimester exposure to hepaDirector of Clinical Genetics and Dysmorphology, Cedars-Sinai titis. Birth weight was 2,155 with a 33 cm head circumMedical Center, 444 S. San Vicente Blvd., Suite 1001, Los Angeles, ference. Family history was negative for BDLS and karyotype was 46,XX normal female. She continued to CA 90048. 0 1993 Wiley-Liss, Inc.

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experience failure to thrive marked by recurrent vomiting and aspiration. Due to markedly slow developmental progress, she underwent residential placement at age 2V2 years. When seen at age 5 years, she was able to stand with support, feed herself and pull to a steady position. Medical problems included a 60-80 dB hearing loss with little response to sound, myopia, pneumonia and regurgitation. She had a polydactylous postaxial digit removed from her right hand. Physical exam at age 5 years showed a weight of 10.77 kg, height 84.5 cm, and head circumference 42 cm (all below the 3rd centile). Her facial anomalies included microcephaly with low frontal hairline, synophrys with long eyelashes, a short nose with anteverted nostrils, notching of the upper lip, lower central alveolar cleft and midface deficiency. Limbs were short relative to trunk, with limited supination of forearms. Hands were short with no distal finger creases and altered transverse palmar creases. She also had generalized hypertrichosis and cutis maromorata. Radiological manifestations. Newborn X-rays showed a skull with microcephaly without evidence of micrognathia. A mandibular spur was present at the mentum (Fig. 1A).The chest was barrel-shaped with 13 ribs. The ribs had thin midportions with posterior downward angulation. The sternum had not yet fused. Spine was normal. The distal radius and ulna were normal bilaterally. There were hypoplastic first metacarpals bilaterally. On the left hand there was generalized mild shortening of the distal phalanges of the second through fifth digits. Hypoplasia of the middle phalanx of the fifth digit was also present. In addition to the hypoplastic first metacarpal, the right hand had postaxial polydactyly. Both the fifth and sixth digits were hypoplastic and the sixth digit was angulated greater than 90 degrees from the axis of the fifth digit. The other digits appeared otherwise normal in shape.

Patient 2: M.A. (Mild Phenotype) This was a 7 % .year old black male born after an uncomplicated pregnancy to a 14-year-oldmother. Past medical history was significant for bilateral inguinal hernia repair, asthma, chronic otitis media and myopia. Physical examination was noteworthy for weight and head circumference below the 3rd centile. Height was at the 25th centile. Measurements of his hands and feet were also less than the 3rd centile. Moderate midface hypoplasia was present with synophrys and arched eyebrows. Bilateral epicanthal folds were present. There was a slight beaking of the upper lip. Nares were anteverted. Teeth were wide-spaced and dysplastic. There was generalized hypertrichosis especially on the back. His upper limbs showed microbrachydactyly with proximally placed small thumbs and bilateral fifth digit clinodactyly. All fingers had clubbing and the nails of both upper and lower limbs were dysplastic. He had bilateral single transverse palmar creases. Developmentally, he walked a t 16 months, used a cup a t 19 months, and fed himself a t 21 months. At age 7% years, he was succeeding in the second grade. Radiological manifestations There was minimal microcephaly with proportional mandible and maxilla. Chest radiograph was normal except for 13 rib pairs. Lower limb long bones were normal. Elbows showed

Fig. 1. A-C mandibular spurs (arrows) in 3 infants between oneday and three-weeks old. D: Note lack of spur in a 3-year-oldpatient.

Fig. 2. A 38-day-oldmale with mandibular spur (arrow).B: Same patient at 4 months of age showing resolution of spur.

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Fig. 3. Chestroentgenogramsof BDLS.A Chronic aspiration in a 15-year-old.B Patient 1 with barrel chest, 13 ribs (not seen here) and downward angulationof the ribs. C: Chronic aspirationwith abnormal appearance of ribs. D 2-year-old with barrel chest. E,F One-month-oldwith cardiomegaly and 13 ribs.

bilateral evidence of repeated radial head dislocation, worsening over a six year period. Distal radius and ulna were normal. Films taken at age one year showed severe carpal ossification delays bilaterally. There were hypoplastic first metacarpals, as well as hypoplasia of the proximal and distal phalanges, bilaterally. Mild hypoplasia of the fifth digit was present on the left side only. Radiographs done at 57/iz years chronological age documented a bone age of 43/iz years.

RESULTS The radiographic manifestations of our 21 cases are tabulated in Table I, and the variability in expression of radiologic manifestations is depicted in Figures 1-7. The totals are based on the number of cases in which there was either a radiograph demonstrating that finding or a documented clinical history; thus, there were 12 cases in which presence or absence of mandibular spurs

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Fig. 4. Lateral x-rays showing shortening of the sternum with abnormal ossification and angulation in

2 mildly affected cases (A) and (B).

could be noted (Figs. 1and 2), and there were 16 cases with anterior views of the chest on which the number of ribs could be counted (Fig. 31, but only 13 lateral views enabling examination of the sternum (Fig. 4). Pattern profiles were done, using the technique described by Garn et al. [19721,Poznanski et al. [19721, and Gefferth [19721. In cases where there were distal limb defects (Figs. 5 and 6), especially phocomelia, transverse hemimelia, and oligodactyly,we considered the hypoplasia of the first metacarpal and fifth middle phalanx to be present if that digit was not obviously and undeniably identifiable and normal. Presence or absence of radial head abnormalities could be judged in 14 cases (Fig. 7). Our data showed increased frequency of hypoplasia of the fifth middle phalanx (93%), distal limb defects (89%),abnormal pattern profile (88%),hypoplasia of the first metacarpal (79%),dislocation and/or hypoplasia of the proximal radius (79%), and microcephaly (75%). There was also frequent observance of clinodactyly of the fifth digit, abnormal length and ossification of the sternum, and 13pairs of ribs. The pattern profile of our patients who were mildly affected are shown in Figure 8. Figure 9 shows the mean profile of our 5 classically affected patients compared to that of 18 patients described by Peeters 119751.

DISCUSSION The classic radiographic manifestations which have been described in BDLS include microcephaly,limb and digit anomalies, delayed skeletal maturation, abnormal thoracic and flat in infancy [Tavbi and Lachman, 19901. Limb anomalies include &c&-jmelia, oligodactyly, and terminal transverse hemimelia. Other digital anomalies include clinodactyly, syndactyly, shortened metacarpals, and

Fig. 5. Variability of distal limb defects. A: Acromelia in mildly affected case, M.E. B: Patient 1,acromelic left hand with hypoplastic 1st metacarDa1 and mild shortening of distal uhalanees (image reversed for pirposes of comparison). Patient 1; acromhc righthand with postaxial polydactyly and hypoplastic 1st metacarpal. D Cleft hand deformity with relatively normal thumb, broad and elongated 3rd metacarpal, and severely dislocated hypoplastic 5th digit.

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Fig. 6. Variability of limb defectswithin patients. A,B:Two-monthold female with probable humeroradial fusion, other extremity with absence of 2nd forearm bone and solitary digit. C,D Three-week-old female with phocomelia, hypoplastic curved humerus, and distal reduction. Other limb had hypoplastic thumb with aplasia of 1st metacarpal, dropout of 3rd and 4th digits, and hypoplastic 5th digit with incurving.

hypoplastic phalanges. These may result in an abnormal pattern profile analysis [Peeters, 19751. Radial subluxation and fixation a t the elbow is also commonly encountered. In 1967, 3 groups published radiological findings in this syndrome [Kurlander and DeMeyer, 1967; Lee and Kenny, 1967; Gerald and Umansky, 19671. The focus of these articles was on the microcephaly, ossification delays, and upper limb defects forming a constellation of findings indicative of, but not specific to, the syndrome. Clinodactyly with hypoplasia of the fifth digit and short broad first metacarpals were found in approximately 90% of cases [Kurlander and DeMeyer, 19671, and with inclusion of proximal radial defects, this was felt to be characteristic of the syndrome. Gerald and Umansky 119671 felt that the key manifestations were microcephaly, micrognathia and bony hypoplasia. Our data correlate well with that which has been previously reported, with the highest frequencies of involvement affecting the head and upper limbs. The wide variety of limb defects noted in the literature is also present in our sample. This consisted of: 6 isolated cases of acromelia in relation to normal standards, one polydactyly, 2 complete losses of the ulnar ray, one preaxial cleft, and 2 terminal transverse hemimelias. Ulnar terminal paraxial hemimelia, though considerably rarer than radial, is more frequently associated with BDLS [Kurlander and DeMeyer, 19671. None of our cases had severe lower limb defects.

Fig. 7. Variability of radial head abnormalities. A Three-year-old classically affected female with hypoplastic and proximally dislocated radius. B. Patient 2 showing effects of repeated radial head dislocation with marked hypoplasia of proximal radius and ulna. C: Thirty-yearold mildly affected male with dislocation and overgrowth of proximal radius. D Three-week-old classically affected female with a hypoplastic dislocated radius and normal ulna. E: Two-year-oldclassically affected male with radial hypoplasia but without current subluxation.

Also present in our group was a high incidence of microcephaly. The majority of our cases had mandibles which were proportional to the maxillas and skulls, therefore, radiographic micrognathia did not exist in our cases, though previous reports include this as a radiologic feature [Gerald and Umansky, 1967; Kurlander and De Myer, 19671. An interesting note was the finding of 5 mandibular spurs (Fig. 1). These were only

Radiology of Brachmann-de Lange Syndrome TABLE I. Radiologic Manifestations of Brachmann-de Lanse Svndrome ~

Findings Microcephaly Mandibular spur Distal limb defects" Dislocatedhypoplastic radial head Abnormal pattern profiles Hypoplastic 1st metacarpal Hypoplastic 5th middle phalanx Clinodactyly 5th digit Short sternum with precocious fusion Thirteen ribs Thin rib cortices with undulating appearance Diaphragmatic herniab Hiatal hernia Aspiration pneumonia-chronic Gastroesophageal refluxl esophageal stricture/esophageal dilatation Intestinal obstruction Pelvic abnormalities in infancy

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No. of cases 12/16 5/12 16/18 11/14 718 11/14 13/14 9/14 7/13

Percent

9/16 5/15 2/18 3/19 5/10 7/12 3/18 319

Terminal transverse hemimelia, oligodactyly, polydactyly, micromelia. One case previously reported by Cunniff et al. [1991].

noted in radiographs done during the first 3 months of age. In one case (Fig. 2) we had a series of mandibular images to observe due to the patient's severe respiratory illnesses. The mandibular spur was observed to disappear as the infant increased in age from 1to 4 months.

We found one radiological reference to this finding [Curtis et al., 19771. In their case, the follow-up study at 3 months showed diminution of the spur. The significance of this finding is unknown, but spurs are rarely seen as a normal variant. We postulate that this is another example of delay in the normal pattern of bone growth and ossification, whose radiographic presence may be beneficial in making difficult newborn diagnoses. We did not find evidence of supracondylar process spurs as reported by Curtis et al. [1977]. Chest anomalies involved the ribs and sternum. Over half of our cases had short sternums with premature fusion, and several others were felt to show early ossification. The 3 mild cases did not have x-rays of their sternums. This may account for the abnormally shaped chest. The frequent occurrence of 13 pairs of ribs has not been described before and should be added to the growing list of common radiologic manifestations of BDLS. Pattern profiles done on 8 cases were consistent in demonstrating shortness of the first metacarpal and fifth distal phalanx, as well as the overall smallness of digits below the mean. The one case closest to the mean was severely affected. The 3 mildly affected cases (M.A., M.E., C.D.) did not have similar profiles. No pathognomonic profile has been reported [Peeters, 19751, but most profiles are abnormal. In reviewing the cases of mild BDLS, it was necessary to exclude other possible diagnoses. F'ryns [19861 suggested that several reports of mild phenotypes might actually represent examples of the Coffin-Siris syndrome, an autosomal dominant condition with mild

Pattern Profiles of Brachmann-De Lange Mild Phenotype

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mental retardation. Clearly, this condition needs to be considered prior to diagnosing cases as having the mild BDLS phenotype. Our mild cases (M.A.,M.E., and C.D.) had micromelia with hypoplastic metacarpals and phalanges. The case described herein (Patient 2) also had dysplastic nails, which are found in Coffin-Siris syndrome. However, as Carey and Hall [19781 reported, Coffin-Siris syndrome includes scalp hypotrichosis and full lips, neither of which were found in our cases.

CONCLUSION In reviewing the data from these 21 cases, the constellation of radiographic manifestations is similar in both severely affected and mildly affected individuals. We also feel that the presence of the 13 pairs of ribs in this syndrome is another key diagnostic finding. It may be practical to look for this extra rib pair during prenatal ultrasonography of a growth retarded fetus with limb anomalies and/or diaphragmatic hernia. In describing the radiologic manifestations of BDLS, we feel that a better awareness of these findings may facilitate the diagnosis of mildly affected individuals. ACKNOWLEDGMENTS We thank Sheila Levin and Ilene Mayo for their help in the preparation of this manuscript. This work was supported in part by a grant from the US.Department of Education, Bureau of Special Education and Rehabilitative Services (HCEEP grant #H024F800017), the New Hampshire Department of Health and Human Services, Bureau of Special Medical Services, and SHARE'S Cedar-Sinai Disability Center.

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