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American Journal of Medical Genetics 47:1175-1179 (1993)

Adams-Oliver Syndrome: A Case With Juvenile Chronic Myelogenous Leukemia and Chylothorax

S.A. Farrell, L.J. Warda, P. LaFlair, and W. Szymonowicz The Division of Genetics (S.A.F.), The Department of Pediatrics (W.S., L.J. W., P.L.), The Credit Valley Hospital, Mississauga, Ontario, Canada

We report on a patient with Adams-Oliver syndrome and report new findings: a chylous pleural effusion and juvenile chronic myelogenous leukemia. Also, our patient had congenital heart disease, confirming that heart lesions are a manifestation in this syndrome. The major manifestations of this disorder are summarized. Included are cases not previously recognized as having Adams- Oliver syndrome identified in a literature sur- vey. Distal limb deficiency is commonest with more frequent and more severe involvement of the lower limbs. Scalp defects are the second commonest manifestation, while an underlying skull defect is not infrequent. Cutis marmorata telangiectatica and dilated scalp veins are significant signs of this condition. This review highlights unresolved questions about Adams-Oliver syndrome. 6 1993 Wiley-Liss, Inc.

KEY WORDS Adams-Oliver syndrome, cutis aplasia, skull defect, cutis marmorata telangiectatica, lymphangiectasia, congenital heart disease, juvenile chronic myelogenous leukemia

INTRODUCTION The combination of limb defects with cutis aplasia of

the scalp characterizes the Adams-Oliver syndrome [Adams and Oliver, 19451. Our case demonstrates 2 new manifestations: chylothorax and a persistently elevated white cell count which at 10 months was diagnosed as juvenile chronic myelogenous leukemia. The manifestations of previously reported patients with Adams-Oliver syndrome are summarized.

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Received for publication February 21, 1993; revision received May 25, 1993.

Address reprint requests to Dr. S. Farrell, Division of Genetics, The Credit Valley Hospital, 2200 Eglinton Avenue West, Mississauga, Ontario, Canada L5M 2N1.

0 1993 Wiley-Liss, Inc.

CLINICAL REPORT This male infant was born at term following an un-

complicated pregnancy to a nonconsanguineous 34- year-old mother and 36-year-old father. Birth weight and height were at the 25th centile and OFC was at the 5th centile. A discrepancy in hand size was obvious, with a shorter right hand (right total hand and midfinger length 5.8 and 2.3 cm; left total hand and midfinger length 6.0 and 2.5 cm) (Fig. 1). On the right, distal digital tapering and tiny nails were seen and radiographs showed small distal phalanges. Both forearms and the left hand appeared normal. The middle and distal phalanges of the 2nd to 5th left toes were absent and the great toenail was small. The right toes appeared short and all nails were hypoplastic (Fig. 2). Overlying the vertex was a 6 cm2 scalp defect while another 1 cm2 defect was located slightly posteriorly. An extensive bruise covered the adjacent skin and surrounding veins were prominent (Fig. 3). The sagittal suture was wide. Cutis marmorata telangiectatica and dilated veins were seen on the abdomen and lower chest. There was a deep blind sacral dimple. Otherwise, his appearance was un- remarkable. Skull radiographs demonstrated a large midline parietal defect. An echocardiogram demonstrated a small secundum atrial septa1 defect. Spinal radiographs, cranial ultrasound, and ophthalmoscopy findings and karyotype were normal.

His neonatal course was complicated by a right chylous pleural effusion. The pleural fluid was creamy. Analysis showed very high triglycerides (26.25 mmol/L) with lymphocytosis (76%). Blasts were not seen. Inter- mittent recurrences required pleural taps on 5 occa- sions, with the last at age 24 days. Leukocytosis of 49 x 109/L was noted after birth. The white blood cell count was persistently elevated, ranging from 2.59 to 6.23 x lo9& and increased during febrile episodes. A marked left shift was evident on each smear and occasional blasts were detected. Chronic juvenile myelogenous leukemia was diagnosed at 9 months. Confirmation was based on results of in vitro cell culture testing. Bone marrow cytogenetic analysis was normal. Initially bone marrow transplantation was successful, but he relapsed and died in blast crisis. An autopsy was not performed.

The parents and sib are healthy and lacked scalp, skin or digital defects. Skull radiographs were declined.

1176 Farrell et al.

Fig. 1. Hands at birth. Fig. 3. Scalp at 2 weeks.

DISCUSSION Adams-Oliver syndrome is characterized by scalp de-

fects and distal limb deficiencies. Marked phenotypic variability has been recognized [F’ryns, 1987; Jones, 19881. We reviewed 102 cases from the literature, including some reported previously as cutis aplasia [Virenque et al., 1960; Vasconez, 1973; Von Loewenich and Miething, 19791 or cutis marmorata [Bjornsdottir et al., 19881.

The most common limb anomaly found in Adams- Oliver syndrome is distal digital hypoplasidaplasia with the spectrum of defects ranging from distal tapering to absence of the hand or foot. Table I documents the distribution of limb anomalies and demonstrates the more frequent involvement of lower limbs; 78% of patients had lower limb anomalies while the upper limbs were affected in 59%. Table I documents the greater severity of defects in the lower limbs compared to the upper limbs, including a higher frequency of bilateral abnormalities. Our patient had defects of the right fingers, while both feet were more severely affected.

Cutis aplasia is a congenital scalp defect commonly found in Adams-Oliver syndrome. Table I1 shows a bias toward reporting cases with scalp defects as the frequency is much lower if propositi are excluded; 56% had scalp defects. Table I1 also describes that 21% have skull defects associated with scalp defects. Prominence of surrounding scalp veins has been seen previously [Whitley and Gorlin, 1991; F’rieden, 19861. The severity of cutis

TABLE I. Limb Defects (Hypoplastic or Absent)*

Location abnormalities Upper limb 60

% with

carpals 3 metacarpals 10 phalanges 54

syndactyly 11 unilateral-left I

-right 7

Lower limb 79 tarsals 10 metatarsals 20

syndactyly 20 unilateral-left 8

-right 1 bilateral 49

nail anomaly 14

bilateral 31

phalanges 69 nail anomaly 25

Upper plus lower limb defects 48 Fig. 2. a: Feet, dorsal view. b Feet, plantar view. * Total cases reviewed 102.

Adams-Oliver Syndrome 1177

TABLE 11. Skull and Scalp Defects*

% when prospositi are

% excluded Scalp defect 73 56 Skull defect 27 21 * Total number of cases = 102; number of familial cases with exclusion of propositi = 43.

aplasia is variable. Most are full thickness skin defects, but defects can be limited to the dermis. Although most scalp defects are uncomplicated, if there is an underlying osseous defect the meninges can be involved [Frieden, 19861. Erosion into the superior sagittal sinus has resulted in life-threatening hemorrhage. Four children with Adams-Oliver syndrome succumbed to this complication [Koiffman et al., 1988; Pincherle, 19381 while case 1 of Chabrolle et al. [19751 required a transfu- sion. Infection of the lesion resulted in death in 2 early cases [Rosenbaum, 1988; Kahn and Olmedo, 19501. The size of scalp defects in cases of Adams-Oliver syndrome ranged from 0.5 to 144 cm2 [Kuster et al., 19881, but most are less than 10 cm.

Generally, the lesion heals by granulation, resulting in a scar with alopecia. Rarely, excision and grafting or use of scalp flaps has been necessary [Demmel, 1975; Sargeant, 19901. Bony defects ossify in the early years [Demmel, 19751. Our patient was born with a full thickness 6 cm2 lesion at the vertex, and a second smaller posteriorly located lesion. There was an underlying skull defect and prominent scalp veins surrounded the area. Granulation of the scalp defect took 10 months. A small skull defect remained at one year.

Cutis marmorata telangiectatica congenita (CMTC) is a vascular anomaly, found in 12% with cases of Adams-Oliver syndrome. Multiple telangiectasias re- sult in skin having a red to cyanosed hue in a reticular pattern, darkening with crying or activity. Hemangi- omas and varicosities can be present. Although usually evident a t birth, infantile onset has been noted [Powell and Su, 19841. For most patients, the appearance of the vascular anomaly improves with increasing age. Histo- pathologic examination demonstrates dilated capil- laries, veins, and lymphatics, in addition to vascular fibrosis, increased number of vessels, venous thrombo- sis, hyperkeratosis, and an increase in vessel number [Way et al., 19741. Usually CMTC lesions are seen on limbs, trunk, face and scalp [Cohen and Zalany, 19881 and show similar distribution in cases of Adams-Oliver syndrome. Our patient had CMTC of the anterior chest and abdomen which faded somewhat during his first year. In addition to being manifestations of Adams- Oliver syndrome, both cutis aplasia and CMTC can occur as isolated defects or can be found in conjunction with other anomalies. Up to 50% of cases of CMTC have additional congenital defects [Paller, 19871. In- triguingly, South and Jacobs [19781 describe a familial association of CMTC with scalp cutis aplasia, but no other abnormalities. It is possible that such reports could represent cases of Adams-Oliver syndrome, given the phenotypic variability of this disorder.

Another vascular anomaly, dilated scalp veins, was recorded in 11% of patients with this syndrome and was also present in our patient. Both dilated scalp veins and CMTC are significant manifestations of Adams-Oliver syndrome, although most authors do not list them as signs of this disorder.

Congenital heart disease has been reported in patients with Adams-Oliver syndrome [Kiister et al., 1988; Farmer and Maxmen, 1960; S a n d et al., 1989; Toriello et al., 1988; Ishikiriyama et al., 1992; Sybert, 19851. Case 1 of Der Kaloustian et al. [1991] had congenital heart disease but this family history was complicated by tetralogy of Fallot in the father. No manifestations of Adams-Oliver syndrome were noted in the father or other relatives. Palzik and Aiello [19851 described a case of possible Adams-Oliver syndrome in a baby with scalp cutis aplasia, ventricular septal defect and pulmonary stenosis, without other anomalies. Our patient had a small atrial septal defect. Eight firm reports of congenital heart defects among 102 cases of Adams-Oliver syndrome indicate a higher incidence of heart defects than the newborn incidence of 1% noted by Keith et al. [19781. This supports the observations of David et al. [19911 and Ishikiriyama et al. [19921 that congenital heart disease is a component of this syndrome.

Chylothorax, the accumulation of chylous fluid in the pleural cavity, is a manifestation of a congenital lymphatic abnormality [Randolph and Gross, 19571. This unusual finding has not been described previously in any case of Adams-Oliver syndrome. Spontaneous reso- lution, as occurred in our patient, has been reported [Randolph and Gross, 1957; Levine, 19891 in children without Adams-Oliver syndrome.

Lymphangiectasia (dilated lymphatics) is another primary lymphatic disorder [Levine, 19893. Although lymphangiectasia has not been reported in Adams- Oliver syndrome, it is described in 2 sibs with scalp cutis aplasia but without limb abnormalities [Bronspiegel et al., 19851. In addition, lymphangiectasia is noted in patients with CMTC. The association of lymphangiectasia with scalp defects, and lymphangiectasia with CMTC creates the question whether lymphangiectasia could be a manifestation of Adams-Oliver syndrome. The pleural effusion of our patient contained lympho- cytes (without blasts) and chyle, all consistent with a chylothorax and not a leukemic pleural effusion. Despite lack of lymphangiectasia elsewhere, presumably this boy’s chylothorax reflects a lymphatic abnormality. The possibility of lymphatic abnormalities should be borne in mind when the diagnosis of Adams-Oliver syndrome is under consideration.

Juvenile chronic myelogenous leukemia is a rare entity in the first months of life [Williams et al., 19831 and has not been described in patients with Adams-Oliver syndrome. It remains to be seen whether this is coincidence.

Usually Adams-Oliver syndrome is described as following an autosomal dominant mode of inheritance [Whitley and Gorlin, 19911. Supporting this pattern of inheritance are 11 firmly diagnosed multigenerational families, with a total of 55 affected relatives. Pedigree analysis documents 7 examples of male-to-male trans- mission. These pedigrees include 3 apparently non-

1178 Farrell et al.

manifesting persons. The ratio of affected to unaffected sibs, with exclusion of probands in these families is 1:1.06 (34:36). Although these multigenerational families are consistent with autosomal dominant inheritance, other observations do not fit this readily. Twenty cases are not firmly familial and some of these have relatives with unusual findings, not entirely diagnostic of Adams-Oliver syndrome. For example, Hidalgo et al. [1983] describe a proband with limb, skull and scalp defects, a great aunt with a scalp defect, and normal intervening relatives. If dominant, the penetrance seems to be low in this pedigree. The reports of families with unaffected parents but more than one affected child [Koiffman et al., 1988; Kahn and Olmedo, 1950; Lynch and Kahn, 1970; Sybert, 19851 led Toriello et al. [1988] to propose causal heterogeneity and Sybert [19891 to consider allelic heterogeneity to be the basis of Adams- Oliver syndrome. As noted by Toriello et al. [1988] linkage analysis is needed to elucidate the genetics of this disorder.

Twenty-seven cases, including ours, were sporadic. The sporadic cases and those with nondiagnostic findings in relatives must be considered in light of the significant phenotypic variability of Adams-Oliver syndrome [Jones, 19881. It is entirely possible that mildly affected relatives were undetected. An illustration of this was provided by Bonafede and Beighton [19791 who docu- ment a radiographic skull defect without an overlying scalp defect as a subtle sign of Adams-Oliver syndrome in a familial case. Given the phenotypic variability and the uncertain penetrance, it is not possible to calculate the exact frequency of familial or isolated cases. These factors make segregation analysis to determine the mode of inheritance difficult.

The biologic basis of Adams-Oliver syndrome is uncertain. Speculation as to the cause of cutis aplasia, a major component of this condition, has been extensive [Frieden, 1986; Sybert, 19851. Possibilities include trauma [Brown et al., 19771, amniotic bands [Pers, 19631, abnormal tissue [Ingalls, 19331, and disruptive forces [Sephan et al., 19821, including vascular disruption [Der Kaloustian et al., 1991; Hoyme et al., 1992; Mannino et al., 1977; Levin et al., 19803. Similar theo- ries have been proposed for the pathogenesis of limb deficiencies. Whitley and Gorlin [19911 suggest an in- trinsic predisposition to interference with normal tissue development. In addition to the classic findings of cutis aplasia and limb deficiencies, we found dilated scalp veins and CMTC frequently to be part of Adams-Oliver syndrome and these signs would be additional indicators of a predisposition to vascular disruption. Since the origin of the lymphatic system is endothelium of adjacent veins [Randolph and Gross, 19571, the chylothorax of our case presumably is another sign of vascular disruption.

This case of Adams-Oliver syndrome extends the phenotype to include new observations, chylothorax, indi- cating the possibility of lymphatic anomalies, and juvenile chronic myelogenous leukemia. Given the rarity of juvenile chronic myelogenous leukemia and Adams- Oliver syndrome, it is unexpected for these 2 problems to occur together bv coincidence but if it is coincidence

patient’s congenital heart disease reinforces the observation that anatomic heart lesions are part of Adams- Oliver syndrome. Still unclear is the biologic basis of the physical signs of this disorder. Our review extends the phenotype to include CMTC and dilated veins and sug- gests some cases are not recognized. A remaining question is whether this disorder is a single entity, hetero- genous, or represents allelic conditions. To analyze this, linkage analysis is necessary. Once the genetic aspects are understood, the full extent of phenotypic variability and penetrance can be assessed.

ACKNOWLEDGMENTS Dr. A. Zipursky of The Hospital for Sick Children,

Toronto, Canada provided helpful discussions. We ap- preciate the office assistance of Ms. F. Falcicchio and Ms. A. Keir. Michelle Baron provided the art work. Transla- tion provided by Dr. Peter Van Rhijn is gratefully ac- knowledged.

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