American Journal of Medical Genetics 40319-326 (1991)
Adams-Oliver Syndrome Revisited Chester B. Whitley and Robert J. Gorlin Departments of Pediatrics (C.B.W., R.J.G.) and Oral Pathology and Genetics (R.J.G.),and Institute Genetics (C.B.W., R.J.G.),University of Minnesota, Minneapolis The occurrence of Adams-Oliver syndrome in a patient from the same geographic area as the first reported kindred led to follow-up of the original family, and to a survey of the literature. Of 81 cases in 32 families, there is an approximately equal distribution between sexes (38males: 43 females).Vertical transmission in at least 8 families is consistent with autosomal dominant inheritance. The phenotype is variable with a range of mild-tosevere defects of the scalp and/or underlying bone. Despite large defects of the cranium, central nervous system abnormalities have not been found and intellectual development appears to be normal. Limb defects are usually limited to the digits, but may involve the long bones and are entirely absent in some obligate carriers of the gene. Cutis marmorata and tortuous, dilated scalp veins have been reported in association with the major head and limb defects, but also in isolation as a forme fruste phenotype. Thus, there is a broad range of variable expression ranging from cases with lethally hemorrhagic cranial defects and/or severe limb malformations, to patients without any apparent manifestations. Despite a phenotypic resemblance to isolated aplasia cutis congenita and to the syndrome of terminal transverse limb defects, Adams-Oliver syndrome appears to be causally distinct. While the underlying pathophysiologic mechanism remains unknown, it can be speculated that cranial vertex defects and malformations of the limbs represent field defects resulting from impaired circulation in “watershed” areas during a critical period of development.
Received for publication July 18,1990;revision received November 14, 1990. Address reprint requests to Chester B. Whitley, Ph.D., M.D., Box 446, University of Minnesota Medical School,420 Delaware Street S.E., Minneapolis, MN 55455.
0 1991 Wiley-Liss, Inc.
of Human
KEY WORDS: Adams-Oliver syndrome, amnion rupture sequence, amniotic bands, aplasia cutis congenita, cranial vertex defect, cutis marmorata, skeletal dysplasia, transverse terminal defects of limbs, vascular disruption INTRODUCTION Autosomal dominant transmission of vertex cranial defects resembling aplasia cutis congenita, in combination with terminal limb malformations, was first reported from Minneapolis by Forrest Adams and C. Peter Oliver in 1945. The recent occurrence of Adams-Oliver syndrome in a patient from the same geographic area prompted us to restudy the original kindred, and to survey the characteristics of all known cases. CLINICAL REPORTS Patient 1 The patient was the 34-week-gestation white male product of a 35-year-oldprimigravid woman, and her 29year-old husband. The pregnancy was uncomplicated, and no medications were taken. Physical examination showed a 2 x 4% cm ulcerated defect of the skin at the cranial vertex, mid-face hypoplasia, “amputated digits of the right hand, digits 4-5 syndactyly of the right foot, fusion of digits 3-5 on the left foot, and a short right sternocleidomastoid with torticollis. The patient’s initial problems included prematurity with respiratory distress treated with mechanical ventilation, systemic antibiotics and otherwise standard care on the newborn intensive care unit. Extensive clinical and laboratory evaluation showed normal cardiac, gastrointestinal, and renal structure and function. Radiographs confirmed the underlying bony defects in the limbs, specifically,the impression of a normal left hand, a right hand with apparent “amputated digits with absent phalanges (Fig. l), the right foot showing45 syndactyly and fusion of digits 3-5 of the left foot. There were moderate contractures of the knees and heels, and slight contractures of the elbows. There were no other skeletal defects save for very thin skull bones with a large anterior fontanel (Fig. 2).
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Fig. 1. Anterior-posteriorradiograph of the right hand showing absence of phalanges and cutaneous syndactyly (Patient 1).
At age 2 days, the ulcerated cranial defect was explored surgically. A yellow membrane was excised with a V4 cm margin of skin exposing the underlying meninges. There was a small hole in the dura adjacent to the sagittal sinus. The operative area was irrigated with antibiotic solution, and hemostasis was obtained. The incision was finally closed in one layer with interrupted mattress sutures of 4-0 Ethilon. The site was bandaged with Bacitracin ointment and healed without complications. Microscopic examination of the excised membrane demonstrated a margin of normal skin confluent with a region of dura-like collagenous matrix. At birth, the cranial and limb defects were presumed to result from amnion rupture sequence, but were later identified by us to be consistent with Adams-Oliver syndrome. Review of the pedigree was unremarkable. The parents denied consanguinity and there was no family history of neurologic, skeletal, or cutaneous disorders. The parents were specifically examined and found to have no cutaneous or palpable skeletal defects of the skull or limbs. Radiographic studies of the parents were declined. Follow-up evaluation of the patient at age 5 years showed slight asymmetry of the skull and face, static abnormalities of the limbs, and normal intellectual progress. Cranial CT scan showed no abnormalities except those related to asymmetry of the skull.
Patient 2 and Original Adams-Oliver Family Upon diagnosis of Patient 1, the geographic proximity to the original kindred of Adams and Oliver 119451 was recognized. Because the proband’sinitials and birthdate
Fig. 2. Lateral and anterior-posteriorskull radiographs showing skull defect at vertex (Patient 1).
were included in the publication, we were able to identify the proband from admission records of the University of Minnesota Hospital. Information was then obtained from the narrative medical record, and from the personal files of Dr. C. Peter Oliver. Although the proband had moved and could not be examined, follow-up data were obtained from the family by telephone including current pedigree information (Fig. 3). During the intervening 45 years, the infant proband 111-23 (in the original pedigree, 111-16)had survived to adulthood, become gainfully employed suffering only minimal disability from limb defects. He used orthotic devices to compensate for below-the-knee congenital deficiency, but had a very satisfactory quality of life. He reported no other significant medical problems. Since the initial report, a fourth generation had been
Adams-Oliver Syndrome Revisited
I
321
T
11
III
IV Fig. 3. Updated family pedigree of the family initially reported by Adams and Oliver [1945].Since the original report, the gene has been transmitted to at least one member of a fourth generation (IV-9).
produced (Fig. 3). The proband‘s affected brother (111-20) had 2 unaffected girls (IV-7 and IV-8) and one affected daughter (IV-9). The affected girl had minimal shortness of the toes bilaterally, but no open skull defect. There were no spontaneous abortionslstillbirths. During the course of this investigation, it was discovered that this kindred was part of an exceedingly large and well-documentedfamily of several hundred individuals. The extended family could be traced to 5 sibs who immigrated from Luxembourg to America in 1852. Individual 1-1was an offspring of one of these immigrants. From inquiries to members of this extended kindred, no other cases of Adams-Oliver syndrome have appeared in other branches of the kindred; 1-1appears to be the new mutation “founder” of the Adams-Oliver allele in this family. Transmission of the gene to 9 affected individuals in 4 generations is consistent with autosomal dominant inheritance, including 5 examples of male-to-male transmission. There was a wide range of severity, including individuals with no recognizable stigmata (1-l), to the proband with relatively severe deficiencies of the lower limbs and open scalp and skull defects (111-23). MATERIALS AND METHODS The literature was surveyed for cases fitting the diagnostic criteria of vertex cranial defects associated with terminal limb malformations. The tabulated data include individuals who can be inferred (on the basis of autosomal dominant transmission) to be a carrier of the gene although lacking phenotypic characteristics. This method of ascertainment specifically excluded cases of vertex aplasia cutis congenita as an isolated finding or due to other known disorders (Table I). Ascertainment also excluded cases of terminal limb malformations as an isolated finding or due t o a known disorder. However,
cases with isolated cranial or limb defects were included if both defects were present in different relatives in a family and explainable on the basis of autosomal dominant transmission. RESULTS AND DISCUSSION The results of this survey are summarized in Table I1 and 81 individuals with phenotypic characteristics of Adams-Oliver syndrome, or relatives who are construed to be obligate carriers of the responsible gene. Although the quantity and quality of available information from different sources was quite variable, some generalizations can be made. Of this group, 52 of the 69 cases (75%) that could be evaluated had typical scalp involvement, 27 of 42 (64%)had existing or healed skull defects, and 61 of 72 (85%)had mild or severe terminal limb defects. These frequencies are biased by the method of ascertain ment, but illustrate that none of the diagnostic abnor.malities is invariably presentdemonstrating variable expressivity . The first report of this disorder was probably that of Pincherle [1938], who described anewborn infant with a large cranial vertex anomaly involving both the scalp and skull, and asymmetric terminal limb defects. As an apparent sporadic case, the anomalies were attributed to amniotic bands. One earlier observation by Lequeux [Engelmann, 19101of an infant with cranial defects and bilateral syndactyly of the toes may have been reporting an Adams-Oliver syndrome, but this case could not be included for lack of sufficient information. The first familial cases were noted by Adams and Oliver [19451 and, even in the context of more recent observations, this family was remarkable for both severity and variability of limb abnormalities. In fact, the proband has the most severe limb reduction abnormal-
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TABLE I. Conditions With Aplasia Cutis Congenita [After Table 13-1, Gorlin et al., 19901
Syndromal Monogenic Adams-Oliver syndrome Postaxial polydactyly Ear anomalies and rudimentary nipples Unilateral facial paresis, dermal sinuses, and ear malformations Johanson-Blizzardsyndrome Setleis syndrome Familial 46,XY gonadal dysgenesis with ectodermal and mesodermal anomalies Ectodermal dysplasia-abnormalfacies Chromosomal Trisomy 13 syndrome del(4p) Disruptive Amnion rupture sequence Infectious Congenital herpes simplex Congenital varicella Teratogenic Methimazole Malformational Central nervous system Hydrocephaly Holoprosencephaly Meningocele Congenital midline porencephaly Early telencephalic defects Occult spinal dysraphism Craniospinal rachischisis Leptomeningeal angiomatosis and aneurysm of distal posterior cerebral artery Cardiovascular system Arteriovenous malformation Congenital heart defects Gastrointestinal system Tracheoesophageal fistula Omphalocele
Intestinal lymphangiectasia Cleft lip-palate Pyloric atresia Other Piebaldism Unknown genesis Focal dermal hypoplasia Ectodermal dysplasias (various types of the tricho-odontoonychial subgroup) Epidermal nevus syndrome Multiple hamartomas, giant pigmented nevocellular nevus, and CNS malformation Oculo-cerebro-cutaneous syndrome Sakati syndrome SDear-Mickle svndrome
ities observed thus far, while other affected members have minimal involvement. Adams and Oliver recognized the similarity to “congenital amputations’’ characterized by Streeter L19301 and now referred to as amnion rupture sequence. In describing the original kindred, Adams and Oliver made 4 key observations: a) this was a distinct entity consisting of the associated vertex defects with terminal limb malformations, b) it had autosomal dominant inheritance, c) there was variable expression even within a single family, and d) proposed that the pathophysiologic mechanism was one of ar-
rested development. Subsequent observations have borne out the veracity of these observations, and suggest that the disorder is distinct from amnion rupture sequence and other conditions associated with aplasia cutis congenita [Frieden, 1986; Gorlin et al., 1990; Sybert, 1985, 19891.
Clinical Phenotype The scalp lesion is frequently the earliest and most important physical finding. At birth, a large and shiny open scalp defect can be easily mistaken for unruptured fetal membranes [Kahn and Olmedo, 1950; Lynch and Kahn, 19701. Although the scalp lesion resembles simple aplasia cutis congenita, it appears to be etiologically distinct [Frieden, 19861. Always at the vertex, the cutaneous defects have ranged in size from 0.5 cm [Scribanu and Temtamy, 19751to 10 cm in diameter [Bonafedeand Beighton, 19791. Such defects may be minimal areas of thin, atrophic skin or deeper lesions that extend from the skin through the skull to the dura. The presence of a skull defect is not necessarily related to an overlying scalp defect. Each lesion has been observed in the absence of the other [Bonafede and Beighton, 1979; Burton et al., 19761. Defects of the calvaria are quite variable, and often detected only radiographically. During infancy, the defect may be inapparent as a “large fontanelle” or widely split sutures. The calvarial bones often fuse with age leaving only a minimal thinning of the skull, or no detectable defect at all. Even in patients with a large scalp defect and/or skull lesion, the brain does not appear to be involved. Normal brain morphology has been shown by radioisotope encephalography [McMurray et al., 19771, cranial CT scan [Shapiro and Escobedo, 1985; Patient 1, current report], and at autopsy [Rosenbaum, 19511. Affected individuals appear to have normal development during childhood, and normal intelligence later. The limb defects are typically asymmetric being more severe in one arm or leg, often with one or more limbs unaffected. The full spectrum of observed defects ranges to hypoplastic nails, cutaneous syndactyly, bony syndactyly, transverse reduction defects, zygodactyly, ectrodactyly, polydactyly, and brachydactyly [Sybert, 19851. Terminal transverse defects may be so minimal as to be almost imperceptible: shortness of any of the digits, or nails that are only somewhat small or grossly hypoplastic. More severe defects include complete absence of a hand or foot, or virtual absence of a limb (hemimelia) as in the original proband [Adams and Oliver, 19451. Radiographic findings are quite variable, but correspond to the external examination; any of the distal limb bones may be represented by osseous syndactyly or rudimentary bones, or may be entirely absent. It has been suggested that visualization of limb defects by ultrasound examination around the 16th week of pregnancy might permit prenatal diagnosis [Koiffmann et al., 19881. Scribanu and Temtamy [19751 suggested that cutis marmorata is a pleiotropic effect of the mutant gene and has been seen in many cases (Table 11).However, this is not a uniform observation and several well-studied patients do not have cutis marmorata [Shapiro and Escobedo, 1985; Patient 1, current report.].
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TABLE 11. Findings in Patients with Adams-Oliver Syndrome
Case 1 2 3 4
5 6 7 8 9 10 11 12 13 14 15 16 17
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66
Kindred and member 1“ Case 1 2b 1-1 11-7 11-9 11-13 11-15 111-12 111-14 111-16 Patient 2” 11-3 3d 11-4 4” Case 1 Case 2 Mother Grandfather Case 3 5‘ 69 Case 2 79 Case 8 gh Case 1 9’ Observation 2 1oi Observation 6 11’ 11-3 11-4 111-2 111-4 12k Case 1 13k Case 2 14k Case 3 15‘ I-1 11-2 111-2 111-5 16” Case 1 Case 2 Case 3 17” Proband 18” 1-8 11-1 11-2 11-4 111-2 111-3 111-4 111-9 IV-3 19p Fall 4 209 Case 3 11-1 21’ 11-4 111-1 IV-2 IV-3 22” Proband 23t Proband, #7 24t Proband, #8 Mother 25t Proband, #10 26t
1-1, #11 1-2 11-1 111-1 IV-1 IV-6 IV-7
v-1
Sex F M M M M M F M M
F F F F F F M M F F F M
F F F F M M
F M F M
F F M F M M M F F M F
F M F F M M M M M M F F F F
F F M M M M F F F M
Scalp1 skull defect(s)
Terminal limb defect(s)
+I+ I +I I I I I +/+ +I+ -1 +I +/+/+/+I +I +I+ +I+ +I+ +I+ +I+ +I I -1I +/+ +I+ +I+ +I+ I -/+
+
+I +/+I+ +I+ +/-
+I+ +I -1 -I+ +I +/-I +I +I
+I+ +I+ -1 -1 -1+/ +I +I+ +/+I +I +I+
I I -1+I +I -I +I
+ + + + + + + +
Other findings
~-
Neonatal death
+-
+ ++ + +
+ + +
+ + + + + ++
+ + + -
Cutis marmorata Neonatal death
Congenital heart disease Dilated and tortuous scalp veins Mottled skin Demise related to hemorrhage from sagittal sinus Only unilateral short toes with symphalangism Cutis marmorata; death at 14 months Cutis marmorata, dilated and tortuous scalp veins Cutis marmorata Cutis marmorata, dilated and tortuous scalp veins Simple pinna (right ear only) Cutis marmorata, simple pinna Prominent and tortuous scalp veins Enlarged and tortuous veins
+ +
+ + +
+
“Affected”: no details
+ +
+ + +
Cutis marmorata
f
-
+ + +
+ +
Supernumerary nipples Supernumerary nipple Small left eye
++
+
Tortuous scalp vessels and cutis marmorata; submucous cleft “Several” greatgreatuncles with “wide-spaced toes”
+
Syndactyly, wide-spaced toes
+-
+-
(Continued)
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Whitley and Gorlin TABLE 11. Findings in Patients with Adams-Oliver Syndrome (continued)
Case _____ 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Frequency
Kindred and member v-3 V-4 27" 1-2 1-3 11-7 111-9 28' IV-13 IV-15 IV-16 29" Proband
Sex F F F F M F M M M M
Scalp1 skull defectk) -I +I -I-I+ -I+/+ +I+/ +I -I-
F F F M
-I-
31"
Mother Patient 1 Patient 2 Patient 3
32"
Patient 1
M
+I+
30"
Terminal limb defect(s)
+/+ +/+
+I+
38M F / 2 & k 81
++ ++ +
Other findings Twin Twin Obligate carrier without clinical stigmata Dilated tortuous veins and large venous sinusoids
+ -
+ + + + 61+
Neonatal death Neonatal death Prominent scalp veins, cutis marmorata, congenital heart defects Only cutis marmorata Cutis marmorata Cutis marmorata, dilated and tortuous scalp veins, transient neonatal seizures (resolved) Short sternocleidomastoid (right) with torticollis, asymmetric skull
72
"Pincherle [19381. 'Adams and Oliver [19451. Current report. dKahn and Olmedo [1950l; Lynch and Kahn [19701. 'Rosenbaum [1951l. 'Conway and Johnson [19561. gFarmer and Maxmen [19601. Walker et al. [l960l. Ollivier and Janvier [1969l. Scribanu and Temtamy 119751. kChabrolle et al. I19751. 'Burton et al. [1976l. "McMurray et al. [1977l. "Fryns et al. [19771. "Bonafede and Beighton [19791. Loewenich and Miething [19741. qIrons and Olson [19801. 'Wilson and Harcus [19821. "Hidalgo et al. [1983l. tSybert [19851. "Shapiro and Escobedo [19851. 'Koiffmann et al. [19881. "Toriello et al. [19881. "Jaeggi et al. 119901.
Farmer and Maxmen [19601 first noted the association of dilated and tortuous scalp veins. Dilated scalp veins were reported in one child as the only apparent scalp abnormality in a mother-son pair presumed to share the Adams-Oliver gene [Toriello et al., 19881. In one patient, a venous flow study demonstrated a superficial venous plexus with normal superficial drainage to the jugular complex [McMurray et al., 19771. Other anomalies have been observed rarely in association with Adams-Oliver syndrome, including simple pinnae [Burton et al., 19761, congenital heart defect [Farmer and Maxmen, 19601,skin tags on toes [Fryns et al., 19771, hemangioma [Farmer and Maxmen, 19603, undescended testes [McMurray et al., 1977; Scribanu and Temtamy, 19751, supernumerary nipples [Wilson and Harcus, 19821,hypoplastic optic nerve [Wilson and Harcus, 19821,aplasia cutis congenita at the knee [Scri-
banu and Temtamy, 19751, and "woolly hair" [Scribanu and Temtamy, 19751. Chromosomes have been normal in every case examined [Bonafede and Beighton, 1979; Irons and Olson, 1980; Jaeggi et al., 1990; McMurray et al., 1977; Scribanu and Temtamy, 1975; Sybert, 1985;Wilson and Harcus, 1982; Patient 1, current report]. Jones et al. [ 19851observed an affected infant with multiple congenital anomalies including terminal limb defects and aplasia cutis congenita involving the flanks. This infant was noted to have a dup(l3p), thus leading to speculation that this might be the genetic locus [Toriello et al., 19881. Because this infant did not meet the operational definition of Adams-Oliver syndrome for this study, this case was excluded from our series; nevertheless, this observation and the association ofvertex scalp and skull defects with trisomy 13 [Abuelo and Feingold, 19691
Adams-Oliver Syndrome Revisited suggests a chromosomal region for further investigation. Inheritance From our review, the syndrome as autosomal dominant inheritance with clear vertical transmission in 8 pedigrees (Table 11) and includes many examples of male-to-male transmission [Adams and Oliver, 1945; Burton et al., 1976; Kahn and Olmedo, 1950; Scribanu and Temtamy, 19751. A family with “probable AdamsOliver syndrome” also shows vertical transmission from a mother to son [Toriello et al., 19881. In some families, multiple affected offspring have been born to a parent in whom expression was so minimal as to be recognized only retrospectively on the basis of obligate carrier status andlor physical findings within the range of normal variation, e.g., short toes, symphalangism [Burton et al., 1976; Hidalgo et al., 1983; Scribanu and Temtamy, 19751. Sporadic cases likely represent new mutations [Farmer and Maxmen, 19601, but, in several cases, the gene was not penetrant LKahn and Olmedo, 1950; Scribanu and Temtamy, 1975; Shapiro and Escobedo, 19851. Thus, in sporadic cases, it is difficult or impossible to distinguish those with a new mutation from those who are inapparent carriers of the gene. This also leaves open the question of possible epistasis and the need of environmental factors (e.g., placental insufficiency) for expression. Some authors have suggested the possibility of autosomal recessive inheritance [Kahn and Olmedo, 1950; Koiffmann et al., 19881 and 4 of the kindreds reviewed include multiple affected offspring to parents without stigmata (Table 11, kindreds 3, 11,21 and 28). Although kindreds with autosomal recessive inheritance cannot be excluded, these kindreds are also explained on the basis of autosomal dominant transmission if the nonpenetrance is considered.
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number of cases [Kahn and Olmedo, 1950; Rosenbaum, 19511. Some lesions appear to be highly vascular. Deep lesions rarely involve the sagittal sinus predisposing to episodes of spontaneous hemorrhage [Chabrolle et al., 1975; Irons and Olson, 19801 but this has been lethal [Pincherle, 1938; Koiffmann et al., 19881and may complicate attempts at surgical care [Kahn and Olemedo, 19503.
In contrast to the scalp, the limb malformations are always superficially “closed”without aplasia cutis cortgenita. Thus, defects of the digits and limbs do not present an unusual risk for hemorrhage or infection. Older patients may require orthotic devices, and conventional orthopedic management should be anticipated and begun appropriately early.
Mechanism The pathophysiologic mechanism of these defects remains unclear, but several mechanisms have been proposed, including predisposition to amniotic rupture sequence, other forms of extrinsic trauma or compression, and vascular compromise. Although no true phenocopies of Adams-Oliver syndrome have been reported, partial phenocopies may provide some insight into the actual developmental defect(s1. Sybert L19851 noted a sporadic case of aplasia cutis congenita with transverse terminal defects of multiple limbs. This patient likely represented a partial phenocopy of Adams-Oliver syndrome resulting from localized extrinsic compression due t o a maternal uterine tumor present during the first trimester. However, this patient differed from the Adams-Oliver phenotype in subtle but important respects: rather than a single vertex skin defect, multiple sites were affected and not the cranial vertex. Furthermore, a small open skin defect was present a t the tip of‘ the fused fingers suggesting an “extrinsic” teratogenic force. Limb defects more characteristic of Adams-Oliver Pathology syndrome have been associated with antileukemic cheIn the scalp lesion, normal skin abuts a well-demar- motherapy which is speculated t o disrupt ectodermalcated “membrane” of atrophic epidermis which is thin, mesenchymal interactions in limb buds [Schafer, 19811. and gradually fades out entirely, exposing a markedly An intrinsic predisposition to interference with normal atrophic corium [Kahn and Olemedo, 1950; Walker et tissue development seems a likely etiology. The associaal., 19601. In the area of the membrane, there is compact tion of cutis marmorata and the dilated andlor tortuous collagen, but with relatively little adipose tissue, and no scalp veins may be additional indicators pointing to an sebaceous or sweat glands. In the atropic portion of the underlying predisposition to vascular compromise in “watershed areas such as the cranial vertex and limbs. scalp, hair follicles are calcified. Treatment ACKNOWLEDGMENTS Many patients with minimal scalp lesions have not We are indebted to Dr. C. Peter Oliver and Dr. Forrest been treated, and a small area of alopecia or thinned Adams for their insight and recollections. calvaria may be the only remnant of a scalp defect in REFERENCES some adults [McMurrayet al., 19771. Minor scalp defects may be treated with daily cleansing of the involved area Abuelo D, Feingold M (1969): Scalp defects in trisomy 13. Clin Pediatr 8416, 417. with applications of antibiotic ointment. Other patients with larger lesions and exposed dura have required Adams FH, Oliver CP (1945): Hereditary deformities in man due to arrested development. J Hered 36:2-7. minor or major (split-thickness or full-thickness) skin grafting procedures to achieve satisfactory closure [Con- Bonafede RP, Beighton P (1979): Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 3:35-41. way and Johnson, 1956; Hidalgo et al., 1983; Kahn and BK, Hauser L, Nadler HL (1976):Congenital scalp defects with Olmedo, 1950; McMurray et al., 1977; Shapiro and Es- Burton distal limb anomalies. J Med Genet 13:446-468. cobedo, 1985; Walker et al., 19601. The major concern is Chabrolle J-P, Lesage B, Roddier A (1975): Aplasie cutaneo-osseusedu an open scalp lesion which presents the possibility for scalp avec anomalie des extremitCs. Ann Pediatr (Paris) 22:613618. sepsis and/or meningitis; this has been lethal in a
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Conway H, Johnson G (1956): Congenital absence of scalp and skull. Ann Surg 144:1035-1044. Engelmann (1910): Berichte aus gynakologischenGesellschaften. Zentralb Gynakol 34:631-634. Farmer AW, Maxmen MD (1960): Congenital absence of skin. Plast Reconstr Surg 25291-297. Frieden IJ (1986): Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol 14:646-660. Fyrns JP, Corbeel L, Van den Berghe H (1977): Congenital scalp defect with distal limb reduction anomalies. Eur J Pediatr 126:289-295. Gorlin RJ,Cohen MM, and Levin LS (1990): “Syndromes of the Head and Neck,” ed 3. New York: Oxford University Press. Hidalgo J E , Greer DM, Johnson DW (1983): Congenital scalp defect with distal limb anomalies: brachydactyly and hypoplastic toes. Plast Reconstr Surg 72:708-711. Irons GB, Olson RM (1980): Aplasia cutis congenita. Plast Reconstr Surg 66:199-203. Jaeggi E, Kind C, Morger R (1990):Congenital scalp and skull defects with terminal transverse limb anomalies (Adams-Oliver syndrome): report of three additional cases. Eur J Pediatr 1 4 9 5 6 5 4 6 6 , Jones KL, Jones OW, Edwards DK (1985): Multiple disruptive structural defects secondary to a genetically determined alteration in vascular development. Proc Greenwood Genet Center 4:86. Kahn EA, Olmedo L (1950):Congenital defect of the scalp, with a note on the closure of the scalp defect. Plast Reconstr Surg 6:435-440. Koiffmann CP, Wajntal A, Huyke BJ, Castro RM (1988): Congenital scalp skull defects with distal limb anomalies (Adams-Oliver syndrome-McKusick 10030):Further evidence of autosomal recessive inheritance. Am J Med Genet 29:263-268. Loewenich V, Miething R (1974):Aplasia cutis congenita. Monatsschr Kinderheilkd 127:319-321. Lynch PJ, Kahn EA (1970): Congenital defects of the scalp: A surgical approach to aplasia cutis congenita. J Neurosurg 33:198-202. McMurray BR, Martin LW, Dignan PS, Fogelson MH (1977): Hereditary aplasia cutis congenita and associated defects. Clin Pediatr 16:610-614.
Ollivier D, Janvier H (1969):Apropos des aghesies cutanees congenitales: Six nouvelles observations. Ann Chir Plast 14:39-44. Pincherle B (1938): Nouveau-nee avec ulceration congenitale du cuir chevelu mutilations multiples des phalanges et syndactylie partielle. Arch Med Enfants 41:96-99. Rosenbaum S (1951): The problem of congenital skin defect. Acta Med Orient 10:209-211. Schafer AL (1981): Teratogenic effects of antileukemic chemotherapy. Arch Intern Med 141514-515. Scribanu N, Temtamy SA (1975): The syndrome of aplasia cutis congenita with terminal, transverse defects of limbs. J Pediatr 87:79-82. Shapiro SD, Escobedo MK (1985): Terminal transverse limb defects with aplasia cutis congenita (Adams-Oliversyndrome). In Shprintzen RJ, Paul NW (eds): “Diagnostic Accuracy: Effect on Treatment Planning.” New York Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS XXI(2):135-142. Streeter GL (1930): Focal deficiencies in fetal tissues and their relation to intrauterine amputation. Publications Carnegie Inst 22:l-44. Sybert VP (1985): Aplasia cutis congenita: A report of 12 new families and review of the literature. Pediatr Dermatol 3:l-14. Sybert VP (1989):Congenital scalp defects with distal limb anomalies (Adams-Oliversyndrome-McKusick 10030): further suggestion of autosomal recessive inheritance (letter to the editor). Am J Med Genet 32:266-267. Toriello HV, Graft RG,Florentine MF, Lacina S, Moore WD (1988): Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome? Am J Med Genet 29:269-276. Walker JC, Koenig JA, Irwin L, Meijer R (1960): Congenital absence of skin (aplasia cutis congenita). Plast Reconstr Surg 26:209-218. Wilson WG, Harcus SJ (1982): Variable expression ofa congenital scalp defectsimalformation syndrome in three generations. In Nyhan WL, Jones KL (eds): “Dysmorphology.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BDOAS XVII(3B):123-128.
Adams-Oliver Syndrome Revisited Chester B. Whitley and Robert J. Gorlin Departments of Pediatrics (C.B.W., R.J.G.) and Oral Pathology and Genetics (R.J.G.),and Institute Genetics (C.B.W., R.J.G.),University of Minnesota, Minneapolis The occurrence of Adams-Oliver syndrome in a patient from the same geographic area as the first reported kindred led to follow-up of the original family, and to a survey of the literature. Of 81 cases in 32 families, there is an approximately equal distribution between sexes (38males: 43 females).Vertical transmission in at least 8 families is consistent with autosomal dominant inheritance. The phenotype is variable with a range of mild-tosevere defects of the scalp and/or underlying bone. Despite large defects of the cranium, central nervous system abnormalities have not been found and intellectual development appears to be normal. Limb defects are usually limited to the digits, but may involve the long bones and are entirely absent in some obligate carriers of the gene. Cutis marmorata and tortuous, dilated scalp veins have been reported in association with the major head and limb defects, but also in isolation as a forme fruste phenotype. Thus, there is a broad range of variable expression ranging from cases with lethally hemorrhagic cranial defects and/or severe limb malformations, to patients without any apparent manifestations. Despite a phenotypic resemblance to isolated aplasia cutis congenita and to the syndrome of terminal transverse limb defects, Adams-Oliver syndrome appears to be causally distinct. While the underlying pathophysiologic mechanism remains unknown, it can be speculated that cranial vertex defects and malformations of the limbs represent field defects resulting from impaired circulation in “watershed” areas during a critical period of development.
Received for publication July 18,1990;revision received November 14, 1990. Address reprint requests to Chester B. Whitley, Ph.D., M.D., Box 446, University of Minnesota Medical School,420 Delaware Street S.E., Minneapolis, MN 55455.
0 1991 Wiley-Liss, Inc.
of Human
KEY WORDS: Adams-Oliver syndrome, amnion rupture sequence, amniotic bands, aplasia cutis congenita, cranial vertex defect, cutis marmorata, skeletal dysplasia, transverse terminal defects of limbs, vascular disruption INTRODUCTION Autosomal dominant transmission of vertex cranial defects resembling aplasia cutis congenita, in combination with terminal limb malformations, was first reported from Minneapolis by Forrest Adams and C. Peter Oliver in 1945. The recent occurrence of Adams-Oliver syndrome in a patient from the same geographic area prompted us to restudy the original kindred, and to survey the characteristics of all known cases. CLINICAL REPORTS Patient 1 The patient was the 34-week-gestation white male product of a 35-year-oldprimigravid woman, and her 29year-old husband. The pregnancy was uncomplicated, and no medications were taken. Physical examination showed a 2 x 4% cm ulcerated defect of the skin at the cranial vertex, mid-face hypoplasia, “amputated digits of the right hand, digits 4-5 syndactyly of the right foot, fusion of digits 3-5 on the left foot, and a short right sternocleidomastoid with torticollis. The patient’s initial problems included prematurity with respiratory distress treated with mechanical ventilation, systemic antibiotics and otherwise standard care on the newborn intensive care unit. Extensive clinical and laboratory evaluation showed normal cardiac, gastrointestinal, and renal structure and function. Radiographs confirmed the underlying bony defects in the limbs, specifically,the impression of a normal left hand, a right hand with apparent “amputated digits with absent phalanges (Fig. l), the right foot showing45 syndactyly and fusion of digits 3-5 of the left foot. There were moderate contractures of the knees and heels, and slight contractures of the elbows. There were no other skeletal defects save for very thin skull bones with a large anterior fontanel (Fig. 2).
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Fig. 1. Anterior-posteriorradiograph of the right hand showing absence of phalanges and cutaneous syndactyly (Patient 1).
At age 2 days, the ulcerated cranial defect was explored surgically. A yellow membrane was excised with a V4 cm margin of skin exposing the underlying meninges. There was a small hole in the dura adjacent to the sagittal sinus. The operative area was irrigated with antibiotic solution, and hemostasis was obtained. The incision was finally closed in one layer with interrupted mattress sutures of 4-0 Ethilon. The site was bandaged with Bacitracin ointment and healed without complications. Microscopic examination of the excised membrane demonstrated a margin of normal skin confluent with a region of dura-like collagenous matrix. At birth, the cranial and limb defects were presumed to result from amnion rupture sequence, but were later identified by us to be consistent with Adams-Oliver syndrome. Review of the pedigree was unremarkable. The parents denied consanguinity and there was no family history of neurologic, skeletal, or cutaneous disorders. The parents were specifically examined and found to have no cutaneous or palpable skeletal defects of the skull or limbs. Radiographic studies of the parents were declined. Follow-up evaluation of the patient at age 5 years showed slight asymmetry of the skull and face, static abnormalities of the limbs, and normal intellectual progress. Cranial CT scan showed no abnormalities except those related to asymmetry of the skull.
Patient 2 and Original Adams-Oliver Family Upon diagnosis of Patient 1, the geographic proximity to the original kindred of Adams and Oliver 119451 was recognized. Because the proband’sinitials and birthdate
Fig. 2. Lateral and anterior-posteriorskull radiographs showing skull defect at vertex (Patient 1).
were included in the publication, we were able to identify the proband from admission records of the University of Minnesota Hospital. Information was then obtained from the narrative medical record, and from the personal files of Dr. C. Peter Oliver. Although the proband had moved and could not be examined, follow-up data were obtained from the family by telephone including current pedigree information (Fig. 3). During the intervening 45 years, the infant proband 111-23 (in the original pedigree, 111-16)had survived to adulthood, become gainfully employed suffering only minimal disability from limb defects. He used orthotic devices to compensate for below-the-knee congenital deficiency, but had a very satisfactory quality of life. He reported no other significant medical problems. Since the initial report, a fourth generation had been
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I
321
T
11
III
IV Fig. 3. Updated family pedigree of the family initially reported by Adams and Oliver [1945].Since the original report, the gene has been transmitted to at least one member of a fourth generation (IV-9).
produced (Fig. 3). The proband‘s affected brother (111-20) had 2 unaffected girls (IV-7 and IV-8) and one affected daughter (IV-9). The affected girl had minimal shortness of the toes bilaterally, but no open skull defect. There were no spontaneous abortionslstillbirths. During the course of this investigation, it was discovered that this kindred was part of an exceedingly large and well-documentedfamily of several hundred individuals. The extended family could be traced to 5 sibs who immigrated from Luxembourg to America in 1852. Individual 1-1was an offspring of one of these immigrants. From inquiries to members of this extended kindred, no other cases of Adams-Oliver syndrome have appeared in other branches of the kindred; 1-1appears to be the new mutation “founder” of the Adams-Oliver allele in this family. Transmission of the gene to 9 affected individuals in 4 generations is consistent with autosomal dominant inheritance, including 5 examples of male-to-male transmission. There was a wide range of severity, including individuals with no recognizable stigmata (1-l), to the proband with relatively severe deficiencies of the lower limbs and open scalp and skull defects (111-23). MATERIALS AND METHODS The literature was surveyed for cases fitting the diagnostic criteria of vertex cranial defects associated with terminal limb malformations. The tabulated data include individuals who can be inferred (on the basis of autosomal dominant transmission) to be a carrier of the gene although lacking phenotypic characteristics. This method of ascertainment specifically excluded cases of vertex aplasia cutis congenita as an isolated finding or due to other known disorders (Table I). Ascertainment also excluded cases of terminal limb malformations as an isolated finding or due t o a known disorder. However,
cases with isolated cranial or limb defects were included if both defects were present in different relatives in a family and explainable on the basis of autosomal dominant transmission. RESULTS AND DISCUSSION The results of this survey are summarized in Table I1 and 81 individuals with phenotypic characteristics of Adams-Oliver syndrome, or relatives who are construed to be obligate carriers of the responsible gene. Although the quantity and quality of available information from different sources was quite variable, some generalizations can be made. Of this group, 52 of the 69 cases (75%) that could be evaluated had typical scalp involvement, 27 of 42 (64%)had existing or healed skull defects, and 61 of 72 (85%)had mild or severe terminal limb defects. These frequencies are biased by the method of ascertain ment, but illustrate that none of the diagnostic abnor.malities is invariably presentdemonstrating variable expressivity . The first report of this disorder was probably that of Pincherle [1938], who described anewborn infant with a large cranial vertex anomaly involving both the scalp and skull, and asymmetric terminal limb defects. As an apparent sporadic case, the anomalies were attributed to amniotic bands. One earlier observation by Lequeux [Engelmann, 19101of an infant with cranial defects and bilateral syndactyly of the toes may have been reporting an Adams-Oliver syndrome, but this case could not be included for lack of sufficient information. The first familial cases were noted by Adams and Oliver [19451 and, even in the context of more recent observations, this family was remarkable for both severity and variability of limb abnormalities. In fact, the proband has the most severe limb reduction abnormal-
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TABLE I. Conditions With Aplasia Cutis Congenita [After Table 13-1, Gorlin et al., 19901
Syndromal Monogenic Adams-Oliver syndrome Postaxial polydactyly Ear anomalies and rudimentary nipples Unilateral facial paresis, dermal sinuses, and ear malformations Johanson-Blizzardsyndrome Setleis syndrome Familial 46,XY gonadal dysgenesis with ectodermal and mesodermal anomalies Ectodermal dysplasia-abnormalfacies Chromosomal Trisomy 13 syndrome del(4p) Disruptive Amnion rupture sequence Infectious Congenital herpes simplex Congenital varicella Teratogenic Methimazole Malformational Central nervous system Hydrocephaly Holoprosencephaly Meningocele Congenital midline porencephaly Early telencephalic defects Occult spinal dysraphism Craniospinal rachischisis Leptomeningeal angiomatosis and aneurysm of distal posterior cerebral artery Cardiovascular system Arteriovenous malformation Congenital heart defects Gastrointestinal system Tracheoesophageal fistula Omphalocele
Intestinal lymphangiectasia Cleft lip-palate Pyloric atresia Other Piebaldism Unknown genesis Focal dermal hypoplasia Ectodermal dysplasias (various types of the tricho-odontoonychial subgroup) Epidermal nevus syndrome Multiple hamartomas, giant pigmented nevocellular nevus, and CNS malformation Oculo-cerebro-cutaneous syndrome Sakati syndrome SDear-Mickle svndrome
ities observed thus far, while other affected members have minimal involvement. Adams and Oliver recognized the similarity to “congenital amputations’’ characterized by Streeter L19301 and now referred to as amnion rupture sequence. In describing the original kindred, Adams and Oliver made 4 key observations: a) this was a distinct entity consisting of the associated vertex defects with terminal limb malformations, b) it had autosomal dominant inheritance, c) there was variable expression even within a single family, and d) proposed that the pathophysiologic mechanism was one of ar-
rested development. Subsequent observations have borne out the veracity of these observations, and suggest that the disorder is distinct from amnion rupture sequence and other conditions associated with aplasia cutis congenita [Frieden, 1986; Gorlin et al., 1990; Sybert, 1985, 19891.
Clinical Phenotype The scalp lesion is frequently the earliest and most important physical finding. At birth, a large and shiny open scalp defect can be easily mistaken for unruptured fetal membranes [Kahn and Olmedo, 1950; Lynch and Kahn, 19701. Although the scalp lesion resembles simple aplasia cutis congenita, it appears to be etiologically distinct [Frieden, 19861. Always at the vertex, the cutaneous defects have ranged in size from 0.5 cm [Scribanu and Temtamy, 19751to 10 cm in diameter [Bonafedeand Beighton, 19791. Such defects may be minimal areas of thin, atrophic skin or deeper lesions that extend from the skin through the skull to the dura. The presence of a skull defect is not necessarily related to an overlying scalp defect. Each lesion has been observed in the absence of the other [Bonafede and Beighton, 1979; Burton et al., 19761. Defects of the calvaria are quite variable, and often detected only radiographically. During infancy, the defect may be inapparent as a “large fontanelle” or widely split sutures. The calvarial bones often fuse with age leaving only a minimal thinning of the skull, or no detectable defect at all. Even in patients with a large scalp defect and/or skull lesion, the brain does not appear to be involved. Normal brain morphology has been shown by radioisotope encephalography [McMurray et al., 19771, cranial CT scan [Shapiro and Escobedo, 1985; Patient 1, current report], and at autopsy [Rosenbaum, 19511. Affected individuals appear to have normal development during childhood, and normal intelligence later. The limb defects are typically asymmetric being more severe in one arm or leg, often with one or more limbs unaffected. The full spectrum of observed defects ranges to hypoplastic nails, cutaneous syndactyly, bony syndactyly, transverse reduction defects, zygodactyly, ectrodactyly, polydactyly, and brachydactyly [Sybert, 19851. Terminal transverse defects may be so minimal as to be almost imperceptible: shortness of any of the digits, or nails that are only somewhat small or grossly hypoplastic. More severe defects include complete absence of a hand or foot, or virtual absence of a limb (hemimelia) as in the original proband [Adams and Oliver, 19451. Radiographic findings are quite variable, but correspond to the external examination; any of the distal limb bones may be represented by osseous syndactyly or rudimentary bones, or may be entirely absent. It has been suggested that visualization of limb defects by ultrasound examination around the 16th week of pregnancy might permit prenatal diagnosis [Koiffmann et al., 19881. Scribanu and Temtamy [19751 suggested that cutis marmorata is a pleiotropic effect of the mutant gene and has been seen in many cases (Table 11).However, this is not a uniform observation and several well-studied patients do not have cutis marmorata [Shapiro and Escobedo, 1985; Patient 1, current report.].
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TABLE 11. Findings in Patients with Adams-Oliver Syndrome
Case 1 2 3 4
5 6 7 8 9 10 11 12 13 14 15 16 17
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66
Kindred and member 1“ Case 1 2b 1-1 11-7 11-9 11-13 11-15 111-12 111-14 111-16 Patient 2” 11-3 3d 11-4 4” Case 1 Case 2 Mother Grandfather Case 3 5‘ 69 Case 2 79 Case 8 gh Case 1 9’ Observation 2 1oi Observation 6 11’ 11-3 11-4 111-2 111-4 12k Case 1 13k Case 2 14k Case 3 15‘ I-1 11-2 111-2 111-5 16” Case 1 Case 2 Case 3 17” Proband 18” 1-8 11-1 11-2 11-4 111-2 111-3 111-4 111-9 IV-3 19p Fall 4 209 Case 3 11-1 21’ 11-4 111-1 IV-2 IV-3 22” Proband 23t Proband, #7 24t Proband, #8 Mother 25t Proband, #10 26t
1-1, #11 1-2 11-1 111-1 IV-1 IV-6 IV-7
v-1
Sex F M M M M M F M M
F F F F F F M M F F F M
F F F F M M
F M F M
F F M F M M M F F M F
F M F F M M M M M M F F F F
F F M M M M F F F M
Scalp1 skull defect(s)
Terminal limb defect(s)
+I+ I +I I I I I +/+ +I+ -1 +I +/+/+/+I +I +I+ +I+ +I+ +I+ +I+ +I I -1I +/+ +I+ +I+ +I+ I -/+
+
+I +/+I+ +I+ +/-
+I+ +I -1 -I+ +I +/-I +I +I
+I+ +I+ -1 -1 -1+/ +I +I+ +/+I +I +I+
I I -1+I +I -I +I
+ + + + + + + +
Other findings
~-
Neonatal death
+-
+ ++ + +
+ + +
+ + + + + ++
+ + + -
Cutis marmorata Neonatal death
Congenital heart disease Dilated and tortuous scalp veins Mottled skin Demise related to hemorrhage from sagittal sinus Only unilateral short toes with symphalangism Cutis marmorata; death at 14 months Cutis marmorata, dilated and tortuous scalp veins Cutis marmorata Cutis marmorata, dilated and tortuous scalp veins Simple pinna (right ear only) Cutis marmorata, simple pinna Prominent and tortuous scalp veins Enlarged and tortuous veins
+ +
+ + +
+
“Affected”: no details
+ +
+ + +
Cutis marmorata
f
-
+ + +
+ +
Supernumerary nipples Supernumerary nipple Small left eye
++
+
Tortuous scalp vessels and cutis marmorata; submucous cleft “Several” greatgreatuncles with “wide-spaced toes”
+
Syndactyly, wide-spaced toes
+-
+-
(Continued)
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Whitley and Gorlin TABLE 11. Findings in Patients with Adams-Oliver Syndrome (continued)
Case _____ 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Frequency
Kindred and member v-3 V-4 27" 1-2 1-3 11-7 111-9 28' IV-13 IV-15 IV-16 29" Proband
Sex F F F F M F M M M M
Scalp1 skull defectk) -I +I -I-I+ -I+/+ +I+/ +I -I-
F F F M
-I-
31"
Mother Patient 1 Patient 2 Patient 3
32"
Patient 1
M
+I+
30"
Terminal limb defect(s)
+/+ +/+
+I+
38M F / 2 & k 81
++ ++ +
Other findings Twin Twin Obligate carrier without clinical stigmata Dilated tortuous veins and large venous sinusoids
+ -
+ + + + 61+
Neonatal death Neonatal death Prominent scalp veins, cutis marmorata, congenital heart defects Only cutis marmorata Cutis marmorata Cutis marmorata, dilated and tortuous scalp veins, transient neonatal seizures (resolved) Short sternocleidomastoid (right) with torticollis, asymmetric skull
72
"Pincherle [19381. 'Adams and Oliver [19451. Current report. dKahn and Olmedo [1950l; Lynch and Kahn [19701. 'Rosenbaum [1951l. 'Conway and Johnson [19561. gFarmer and Maxmen [19601. Walker et al. [l960l. Ollivier and Janvier [1969l. Scribanu and Temtamy 119751. kChabrolle et al. I19751. 'Burton et al. [1976l. "McMurray et al. [1977l. "Fryns et al. [19771. "Bonafede and Beighton [19791. Loewenich and Miething [19741. qIrons and Olson [19801. 'Wilson and Harcus [19821. "Hidalgo et al. [1983l. tSybert [19851. "Shapiro and Escobedo [19851. 'Koiffmann et al. [19881. "Toriello et al. [19881. "Jaeggi et al. 119901.
Farmer and Maxmen [19601 first noted the association of dilated and tortuous scalp veins. Dilated scalp veins were reported in one child as the only apparent scalp abnormality in a mother-son pair presumed to share the Adams-Oliver gene [Toriello et al., 19881. In one patient, a venous flow study demonstrated a superficial venous plexus with normal superficial drainage to the jugular complex [McMurray et al., 19771. Other anomalies have been observed rarely in association with Adams-Oliver syndrome, including simple pinnae [Burton et al., 19761, congenital heart defect [Farmer and Maxmen, 19601,skin tags on toes [Fryns et al., 19771, hemangioma [Farmer and Maxmen, 19603, undescended testes [McMurray et al., 1977; Scribanu and Temtamy, 19751, supernumerary nipples [Wilson and Harcus, 19821,hypoplastic optic nerve [Wilson and Harcus, 19821,aplasia cutis congenita at the knee [Scri-
banu and Temtamy, 19751, and "woolly hair" [Scribanu and Temtamy, 19751. Chromosomes have been normal in every case examined [Bonafede and Beighton, 1979; Irons and Olson, 1980; Jaeggi et al., 1990; McMurray et al., 1977; Scribanu and Temtamy, 1975; Sybert, 1985;Wilson and Harcus, 1982; Patient 1, current report]. Jones et al. [ 19851observed an affected infant with multiple congenital anomalies including terminal limb defects and aplasia cutis congenita involving the flanks. This infant was noted to have a dup(l3p), thus leading to speculation that this might be the genetic locus [Toriello et al., 19881. Because this infant did not meet the operational definition of Adams-Oliver syndrome for this study, this case was excluded from our series; nevertheless, this observation and the association ofvertex scalp and skull defects with trisomy 13 [Abuelo and Feingold, 19691
Adams-Oliver Syndrome Revisited suggests a chromosomal region for further investigation. Inheritance From our review, the syndrome as autosomal dominant inheritance with clear vertical transmission in 8 pedigrees (Table 11) and includes many examples of male-to-male transmission [Adams and Oliver, 1945; Burton et al., 1976; Kahn and Olmedo, 1950; Scribanu and Temtamy, 19751. A family with “probable AdamsOliver syndrome” also shows vertical transmission from a mother to son [Toriello et al., 19881. In some families, multiple affected offspring have been born to a parent in whom expression was so minimal as to be recognized only retrospectively on the basis of obligate carrier status andlor physical findings within the range of normal variation, e.g., short toes, symphalangism [Burton et al., 1976; Hidalgo et al., 1983; Scribanu and Temtamy, 19751. Sporadic cases likely represent new mutations [Farmer and Maxmen, 19601, but, in several cases, the gene was not penetrant LKahn and Olmedo, 1950; Scribanu and Temtamy, 1975; Shapiro and Escobedo, 19851. Thus, in sporadic cases, it is difficult or impossible to distinguish those with a new mutation from those who are inapparent carriers of the gene. This also leaves open the question of possible epistasis and the need of environmental factors (e.g., placental insufficiency) for expression. Some authors have suggested the possibility of autosomal recessive inheritance [Kahn and Olmedo, 1950; Koiffmann et al., 19881 and 4 of the kindreds reviewed include multiple affected offspring to parents without stigmata (Table 11, kindreds 3, 11,21 and 28). Although kindreds with autosomal recessive inheritance cannot be excluded, these kindreds are also explained on the basis of autosomal dominant transmission if the nonpenetrance is considered.
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number of cases [Kahn and Olmedo, 1950; Rosenbaum, 19511. Some lesions appear to be highly vascular. Deep lesions rarely involve the sagittal sinus predisposing to episodes of spontaneous hemorrhage [Chabrolle et al., 1975; Irons and Olson, 19801 but this has been lethal [Pincherle, 1938; Koiffmann et al., 19881and may complicate attempts at surgical care [Kahn and Olemedo, 19503.
In contrast to the scalp, the limb malformations are always superficially “closed”without aplasia cutis cortgenita. Thus, defects of the digits and limbs do not present an unusual risk for hemorrhage or infection. Older patients may require orthotic devices, and conventional orthopedic management should be anticipated and begun appropriately early.
Mechanism The pathophysiologic mechanism of these defects remains unclear, but several mechanisms have been proposed, including predisposition to amniotic rupture sequence, other forms of extrinsic trauma or compression, and vascular compromise. Although no true phenocopies of Adams-Oliver syndrome have been reported, partial phenocopies may provide some insight into the actual developmental defect(s1. Sybert L19851 noted a sporadic case of aplasia cutis congenita with transverse terminal defects of multiple limbs. This patient likely represented a partial phenocopy of Adams-Oliver syndrome resulting from localized extrinsic compression due t o a maternal uterine tumor present during the first trimester. However, this patient differed from the Adams-Oliver phenotype in subtle but important respects: rather than a single vertex skin defect, multiple sites were affected and not the cranial vertex. Furthermore, a small open skin defect was present a t the tip of‘ the fused fingers suggesting an “extrinsic” teratogenic force. Limb defects more characteristic of Adams-Oliver Pathology syndrome have been associated with antileukemic cheIn the scalp lesion, normal skin abuts a well-demar- motherapy which is speculated t o disrupt ectodermalcated “membrane” of atrophic epidermis which is thin, mesenchymal interactions in limb buds [Schafer, 19811. and gradually fades out entirely, exposing a markedly An intrinsic predisposition to interference with normal atrophic corium [Kahn and Olemedo, 1950; Walker et tissue development seems a likely etiology. The associaal., 19601. In the area of the membrane, there is compact tion of cutis marmorata and the dilated andlor tortuous collagen, but with relatively little adipose tissue, and no scalp veins may be additional indicators pointing to an sebaceous or sweat glands. In the atropic portion of the underlying predisposition to vascular compromise in “watershed areas such as the cranial vertex and limbs. scalp, hair follicles are calcified. Treatment ACKNOWLEDGMENTS Many patients with minimal scalp lesions have not We are indebted to Dr. C. Peter Oliver and Dr. Forrest been treated, and a small area of alopecia or thinned Adams for their insight and recollections. calvaria may be the only remnant of a scalp defect in REFERENCES some adults [McMurrayet al., 19771. Minor scalp defects may be treated with daily cleansing of the involved area Abuelo D, Feingold M (1969): Scalp defects in trisomy 13. Clin Pediatr 8416, 417. with applications of antibiotic ointment. Other patients with larger lesions and exposed dura have required Adams FH, Oliver CP (1945): Hereditary deformities in man due to arrested development. J Hered 36:2-7. minor or major (split-thickness or full-thickness) skin grafting procedures to achieve satisfactory closure [Con- Bonafede RP, Beighton P (1979): Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 3:35-41. way and Johnson, 1956; Hidalgo et al., 1983; Kahn and BK, Hauser L, Nadler HL (1976):Congenital scalp defects with Olmedo, 1950; McMurray et al., 1977; Shapiro and Es- Burton distal limb anomalies. J Med Genet 13:446-468. cobedo, 1985; Walker et al., 19601. The major concern is Chabrolle J-P, Lesage B, Roddier A (1975): Aplasie cutaneo-osseusedu an open scalp lesion which presents the possibility for scalp avec anomalie des extremitCs. Ann Pediatr (Paris) 22:613618. sepsis and/or meningitis; this has been lethal in a
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