American Journal of Medical Genetics 11:319-328 (1982)

Aplasia Cutis Congenita in Two Sibs Discordant for Pyloric Atresia

R. Carmi, S. Sofer, M. Karplus, Y. Ben-Yakar, D. Mahler, H. Zirkin, and J. Bar-Ziv Department of Pediatrics (R. C.), Neonatology (S.S., M. K.), Plastic Surgery (Y.6.-Y., D. M.), Pathology (H.Z.), and Pediatric Radiology (J. B-2.); The Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

We report two sibs who were the products of a consanguineous mating, and who had an extensive form of aplasia cutis congenita (ACC). In one of them the generalized skin disorder was manifested by slipping off of the epidermis and mucous membranes with the slightest trauma. This sib also had pyloric atresia and other congenital malformations. Two hypotheses are presented to explain the discordance between the siblings for the abnormalities other than the ACC. One hypothesis assumes varying degrees of severity of the same autosomal recessive disease. The second suggests linkage between the gene for ACC and the gene for an epidermolysis bullosa (EB)-like disorder and pyloric atresia. A recombination event involving the EB-pyloric atresia gene in one carrier parent would then lead to an offspring with only ACC. Prenatal diagnosis is suggested by monitoring a-fetoprotein levels in amniotic fluid.

Key words: aplasia cutis congenita, pyloric atresia, esophageal atresia, epidermolysis bullosa, con- sanguinous marriage

INTRODUCTION

Aplasia cutis congenita (ACC), a congenital skin disorder manifested by sharply demarcated areas of absence of skin, exists in two forms. In the more frequent one, the defect is usually limited to the scalp, and the suggested mode of inheritance is autosomal dominant [l-31. The second, more extensive form, affects the trunk and limbs, and only recently was discovered to have an autosomal recessive pattern of inheritance [4].

Received for publication March 5 , 1981; revision received July 9, 1981.

Address reprint requests to Dr. Rivka Carmi, Children’s Hospital Medical Center, Birth Defects Center- Fegan 11, 300 Longwood Avenue, Boston, Massachusetts.

0148-7299/82/1103-0319$03.000 1982 Alan R. Liss, Inc.

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Another rather unique form of this disease was described by Bart et a1 [5 , 61, who reported a kinship with the extensive form of ACC and associated skin abnormalities resembling epidermolysis bullosa. The suggested mode of inheritance was autosomal dominant with complete penetrance and variable expressivity.

Pyloric atresia, a rather rare congenital abnormality was not described with ACC. However, pyloric atresia with epidermolysis bullosa of the junctional type (atrophicans) is now a well-recognized disease entity with presumably autosomal recessive inheritance [23-261.

We present two sibs with the extensive form of ACC born to a consanguineous couple. While the first had the rather “classical” disease, the other had associated abnormalities including skin changes resembling epidermolysis bullosa and pyloric atresia.

Patient 1

The infant was prematurely born to healthy, 24-year-old Bedouin parents. The parents were first cousins and had two other children, one who was a 4-year-old girl with chronic idiopathic thrombocytopenic purpura. There was no family history of skin problems or any other diseases. Pregnancy was uncomplicated and delivery was spontaneous from a vertex presentation. Apgar score at 1 min was 8.

Examination. Preterm female infant with estimated gestational age of 29 weeks, birth weight 980 gm, and occipito-frontal head circumference (OFC) of 26.5 cm. Skin was absent from toes to middle of thighs; only the tips of the toes on the right foot were spared (Figs. la, b). Skin was also absent from the dorsum of the right hand and wrist (Fig. lb), and from the right and left sides of the anterior upper neck (Figs. lc, d). The skin on the tip of the nose was absent as well (Fig. lc). All areas of absent skin were covered by a thin, smooth, reddish transparent membrane. The ear lobes which were included in the areas of absent skin were deformed (Figs. lc, d).

The infant died at 36 hr of severe respiratory distress. Cytogenetic study showed a normal female chromosome constitution (46, XX).

Patient 2

The brother of Patient 1 was born prematurely 1 year later after an uncomplicated pregnancy. Delivery was spontaneous from a vertex presentation. Apgar score at 1 min was 1 and the infant required resuscitation. He received oxygen for respiratory distress and hypoxemia.

Examination. Premature infant with estimated gestational age of 30 weeks, weight 1200 gm, and OFC of 28.5 cm. Sharply demarcated areas of absence of skin were noted at the base of the nose bilaterally, on the left lateral aspect of the neck, on the dorsum of the hands, around the wrists, around the umbilicus, and on the penis and gluteal areas. Absence of skin was also observed on the right leg as high as the lower third of the thighs except for the lateral aspect of the foot and tips of toes, on the dorsal aspect of the forefoot, and around the ankle of the lower left limb (Fig. 2a). The denuded areas of the lower limbs were of relatively narrow circumference (Fig. 2a). A fine transparent membrane was present over all of the denuded areas. In addition, the other “normal” areas of the skin, including the oral mucous membrane, showed a strongly positive Nikolsky test as evidenced by a peeling off of the skin with even a light touch (Fig. 2a). No blisters were noted.

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Other anomalies were a small nose with narrow nostrils, absence of the left ear lobe with a small external auditory meatus, and hypoplastic right ear. The external geni- talia resembled those of a male, but with absent scrota1 sac (although there was a different skin texture at the expected location of the scrotum). No testes were palpable. The fingernails on both hands and feet were hypoplastic.

Abdominal and chest roentgenograms, performed because of large amounts of secretions in the infant’s mouth, showed absence of air in the abdomen. Introduction of air and Dianosyl via catheter into the cervical esophagus demonstrated a narrow proximal esophagus with a complete stop at the level of T2. Some of the dye was aspirated into the trachea. Radiographs of the lower limbs showed hypoplasia of soft tissues and bones at the denuded skin areas (Fig. 2d). The infant had a normal chromosome male constitution (46,XY). He died on the third day.

A thorough physical examination of the parents and the other siblings failed to reveal any recent or past evidence of skin, hair, or nail abnormalities. In the subsequent pregnancy of the mother, an amniocentesis was performed which showed normal a-fetoprotein levels and a normal male infant was born.

Autopsy Findings

While Patient 1 did not have any external or internal malformations, Patient 2 had, in addition to the above-mentioned anomalies, atresia of the pylorus, and distal esophagus without tracheoesophageal fistula. No gonadal tissue was found.

Microscopic study of the skin showed a similar pattern in both cases. An abrupt transition was noticed between regions of normal skin and areas of absent skin (Figs. lc, 2b). The normal skin was characterized by the presence of epidermis and dermal appendages in the usual amount (Figs. le, 2b). In the areas of absent skin there was complete loss of epidermis and almost total absence of skin appendages (Figs. le, 2b). The dermal collagen near the surface in these areas was more dense and homogeneous than normal. There was a cellular infiltrate of the upper dermis consisting mainly of lympyhocytes, histiocytes, and fibroblasts (Figs. If, 2c). The dermal and subcutaneous blood vessels appeared dilated and congested with erythrocytes. The subcutaneous adipose tissue contained a diffuse infiltrate of histiocytes and fibroblasts (Figs. If, 2c).

Microscopic study of the peeled skin suggested the roof of a blister. There was a keratin layer, a granulosa layer and two to three Malpighi layers.

DISCUSSION

ACC is a rare condition with two main forms. The more frequent form is usually confined to the scalp at or near the midline, and appears as a hairless scar. Autosomal dominant inheritance is suggested in this type [7, 81. The second form affects larger areas of body surface, mostly the trunk and lower limbs. The lesions tend to be symmetrically distributed [9,10]. Although once described in an offspring of a con- sanguineous mating [ll], there was no clear evidence for a certain form of inheritance until recently, when this form of ACC was described in six persons in three generations of a single inbred family, suggesting autosomal recessive inheritance 141.

Ordinarily neither of the forms shows a blistering tendency. On the other hand, in some cases of fulminating epidermolysis bullosa (EB), localized areas of absent skin were observed [6,12]. The occurrence of blisters with subsequent skin defects [13] and

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Fig. 1. (a-d) Large areas of symmetrically absent skin on the limbs, face, and neck regions. Notice the severely deformed and hypoplastic ears. (e) Low magnification of skin at margin of denuded area showing loss of epidermis. Note also condensation of dermal collagen and inflammatory cellular infiltrate (H & E x 100). (4 Higher magnification of same area. The inflammatory cells are mainly lymphocytes and histiocytes (H & E x 250).

of bullae on the scalp of aborted fetuses [14] and newborn infants [15] suggests that the EB-like skin manifestations might precede the skin “ulcers” of congenital absence of skin which, in turn, might be a result of in utero blistering.

In 1966 Bart et al reported a large kindred dominantly inherited and variably ex- pressed congenital absence of skin, blistering of skin and mucous membranes, and de- formity of the nails [5 ] . They reviewed 19 previous reports describing the lethal form of EB and concluded that the kindred under study had a new syndrome differing from ACC and from various forms of EB, although they noted similarity of the blistering in this syndrome with that seen in the lethal form of EB.

Congenital anomalies such as cleft lip, cleft palate, colobomas, microphthalmia, polydactyly, syndactyly, ear malformations, hydrocephalus [ 14, 16-1 91, spastic paraly- sis and mental retardation [20], and tracheoesophageal fistule [B] have been described in association with ACC.

Recessive Aplasia Cutis 323

Figure 1.

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Figure 1.

Pyloric atresia, a rather rare congenital anomaly of the alimentary tract representing about 1070 of all intestinal atresias, has not been described in association with ACC. However, the association of pyloric atresia and EB, probably of the junctional (atrophicans) type [29], is now well recognized. Since autosomal recessive inheritance for isolated pyloric atresia has been reported [21], some favor a genetic linkage in those cases with both EB and pyloric atresia [29]. However, other reports [23-261 are rather suggestive of these conditions representing one disease entity.

Recessive Aplasia Cutis 325

Fig. 2. (a) Large rather symmetrical denuded skin areas on the face, neck, trunk, and limbs. (b) Low magnification. Margin of denuded area. Histological findings similar to Case 1 (H & X x 100). (c) Higher magnification of higher of previously described area (H & E x 250). (d) Hypoplasia of soft tissues and bones at the areas of skin aplasia.

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Figure 2.

In the present report, both infants had the extensive form of ACC, and since they are products of consanguineous mating, they further support the suggestion of autosomal recessive inheritance in this disorder 141. However, while the first infant showed the rather “dassic” picture of extensive ACC with intervening areas of normal skin, the second infant had apparently no normal skin at all. Though without blisters, his skin and mucous membranes readily peeled after the lightest touch,

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leaving denuded areas (Nikolsky sign). Histologically, this peeled skin was compatible with the roof of a blister and might have presented an EB-like skin defect of such severity that no bullae were formed. In addition, this infant had associated congenital anomalies, some of which (ear deformities, hypoplastic nails) had already been described with ACC, while other (esophageal and pyloric atresia) were not.

Two explanations are suggested for the different clinical manifestations of these two sibs. The first assumes that both were homozygous for the same mutant allele which is responsible for a basic generalized epithelial defect affecting the ectoderm most prominently but also the endoderm to some extent.

Such a generalized severe epithelial defect with, and even without bullae formation in utero might lead to large skin defects over body areas exposed to frequent pressure or friction. Thus, fetal movements with rubbing of the limbs against each other and against the trunk and face might result in absent skin in a pattern similar to the one observed in the two sibs. The same pathogenic sequence of events would be capable of disrupting embryonic and fetal development of many other organs which would explain the other congenital abnormalities reported in association with ACC and partially present in the second sib, For example, presence of the ectodermal defect on premaxillary and maxillary shelves might impair the epithelial integrity required for lip and palate closure. Also mucosal slippage and cicatrization at narrowest sphincter points lead to luminal occlusion with subsequent atresia. Similarly, ependymal defects might result in obstructive hydrocephalus with subsequent mental retardation and spastic quadraplagia, and so on for many other anomalies. By postulating one recessive disease in both sibs one assumes the second sib to be more severely affected. Thus, his associated congenital malformations and the EB-like skin changes are respectively intrauterine and postnatal manifestations of this increase in severity.

The second explanation postulates genetic linkage between two different loci, one for ACC, and the second for EB and pyloric atresia. Gedde-Dahl and Anton- Lamprecht [29] point out the epidemiological fact that families with the combined syndrome of EB and pyloric atresia have so far been of two ethnic groups (American-Indian and Lebanese-Turkish) thus favoring genetic linkage between two autosomal recessive genes rather than a single syndrome. However, other reports on the combined syndrome of EB and pyloric atresia strongly suggest that this is a single autosomal recessive disorder [23-261. In particular, Adashi et a1 [22] reported an electron microscopically proven case of junctional epidermolysis bullosa with wide- spread dystrophic features, where the pyloric atresia was shown to be a result of intense proliferation of connective tissue.

Assuming the coexistence of two well-recognized autosomal recessive disorders, namely, ACC and EB-pyloric atresia in the second sib, and only ACC in the first, one can speculate on linkage between the two genes for these diseases carried by first cousin parents. A cross-over event in either one of the parents involving only the gene locus for EB and pyloric atresia, and not the locus for ACC could have resulted in the first sib with only ACC. This sib would then be heterozygous at the locus for EB and pyloric atresia. Although a single pathognomonic explanation is genetically most likely, the possibility of linkage between two recessive genes cannot be disregarded in such a rare case.

Prenatal monitoring of a-fetoprotein level in amniotic fluid seems to be a promising method for early detection of ACC. It has already been shown that extracellular fluid transudation normally occurs during the first half of pregnancy [27,28]. If one assumes that denuded areas of absent skin behave like burns, then one

328 Carmi et al

can find higher than normal levels of a-fetoprotein, the embryonic albumin, in amniotic fluid. This mode of prenatal diagnosis might be suggested for other families with a history of the extensive form of ACC.

ACKNOWLEDGMENTS

The authors wish to acknowledge Pam Hawley and Pat Freda from Children’s Hospital Medical Center, Boston, Massachusetts, for their help.

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