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Keywords:

  • Golz-Gorlin syndrome;
  • focal dermal hypoplasia;
  • pentalogy of Cantrell;
  • anophthalmia;
  • facial clefts;
  • limb malformations;
  • PORCN

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Goltz–Gorlin syndrome is a highly variable disorder affecting many body parts of meso-ectodermal origin. Mutations in X-linked PORCN have been identified in almost all patients with a classical Goltz–Gorlin phenotype. The pentalogy of Cantrell is an infrequently described congenital disorder characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect; absent or cleft lower part of the sternum; deficiency of the diaphragmatic pericardium; deficiency of the anterior diaphragm; and congenital heart anomalies. Etiology and pathogenesis are unknown. We report on an infant with findings fitting both Goltz–Gorlin syndrome (sparse hair; anophthalmia; clefting; bifid nose; irregular vermillion of both lips; asymmetrical limb malformations; caudal appendage; linear aplastic skin defects; unilateral hearing loss) and the pentalogy of Cantrell (absent lower sternum; anterior diaphragmatic hernia; ectopia cordis; omphalocele). The clinical diagnosis Goltz–Gorlin syndrome was confirmed molecularly by a point mutation in PORCN (c.727C>T). The presence of molecularly confirmed Goltz–Gorlin syndrome and pentalogy of Cantrell in a single patient has been reported twice before. The present patient confirms that the pentalogy of Cantrell can be caused in some patients by a PORCN mutation. It remains at present uncertain whether this can be explained by the type or localization of the mutation within PORCN, or whether the co-occurrence of the two entities is additionally determined by mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences. © 2011 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Goltz–Gorlin syndrome is a highly variable disorder affecting many body systems of meso-ectodermal origin. Major manifestations include atrophic or hypoplastic linear skin lesions with fat herniation, papillomas around orifices, microphthalmia and ocular coloboma, hypodontia, hearing loss, and extremely variable limb malformations [Hennekam et al., 2010]. In addition, other malformations may be found such as underdeveloped mammae, urinary tract defects, facial cleft, cleft lip and palate, caudal tails and anal malpositioning. Intellectual functioning is usually normal or mildly delayed. Variation of expressivity is evident. Mutations in the X-linked PORCN gene can be identified in all patients with a classical Goltz–Gorlin phenotype [Maas et al., 2009]. No obvious genotype-phenotype correlation has been observed to date [Lombardi et al., submitted for publication].

The pentalogy of Cantrell (Cantrell–Haller–Ravitsch syndrome) is a rare, severe and usually lethal congenital disorder, the incidence being estimated at 1 in 65,000 live births. The condition is characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect (i.e., omphalocele, gastroschisis, absent umbilicus, diastasis of the recti); defect of lower sternum (i.e., absent or cleft sternum); deficiency of the diaphragmatic pericardium (ectopia cordis, free communication between pericardial and peritoneal cavities), deficiency of the anterior diaphragm (i.e., anterior diaphragmatic hernia, hypoplastic diaphragm); and congenital heart anomalies (i.e., ASD, VSD, AS, Fallot tetralogy, double outlet right ventricle, truncus arteriosus, anomalous pulmonary venous drainage, left ventricular diverticulum, hypoplastic left heart, tricuspid atresia). Cantrell pentalogy is often incompletely present: the full pentalogy is diagnosed rarely, as various combinations of two or three of four defects of the pentalogy are more common [Cantrell et al., 1958; Toyama, 1972; van Allen et al., 1987; Vanamo et al., 1991; Carmi and Boughman, 1992; Fernandez et al., 1997; Polat et al., 2005; van Hoorn et al., 2008].

We describe a female infant with severe developmental abnormalities resembling Cantrell pentalogy as well as distinctive facial and limb manifestations, clinically diagnosed as Goltz–Gorlin syndrome. Molecular analysis revealed a sporadic point mutation in PORCN. We review the existing literature describing patients with phenotypes that show an overlap with the two entities.

CLINICAL REPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The proposita was born by cesarean delivery because of suspicion of omphalocele at 38 weeks of gestation to a 29-year-old G2P1 mother and a 32-year-old father. Routine fetal ultrasound at 22nd week of gestation had shown intrauterine growth retardation and suggested cleft hands. The remainder of the fetal anatomy appeared normal at that time. At birth she weighted 2060 g (<3rd centile), the length was 46 cm (10th–25th centile), and OFC was 30 cm (<3rd centile). The placenta did not show abnormalities. Physical examination showed absence of lower sternum with intact manubrium, ectopia cordis, presence of the pericardium, midline abdominal skin defect, omphalocele (Fig. 1a,b) and unusual face: asymmetry, bilateral clefts running laterally towards external auditory canals, sparse hair, thin unfolded ears with detached tragus, very deeply set eyes, bifid nose, midline cleft of upper lip, and irregular upper and lower vermillion (Fig. 1c,d). Limbs malformations included limited clefting of the hands, overlapping fingers, camptodactyly and absent or malformed nails, and split right foot, underdeveloped hallux, complete syndactyly of second and third toes and fourth and fifth toes on the right, and small hallux and, over-riding toes on the left as well as bullous abnormalities on the toes of both feet were observed (Fig. 2b–d). Further examination showed underdeveloped labia majora, asymmetric position of urethral orifice, caudal appendage, and imperforate anus (Fig. 2a). Areas with dermal hypoplasia were present on her back, left elbow, and left popliteal fossa, and also linear areas of hypoplastic skin were observed on the lower limbs and acra (Figs. 1a,b and 2c,d).

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Figure 1. Manifestations of Goltz–Gorlin syndrome and Cantrell pentalogy in the present proposita. a: The thorax/abdomen before surgery showing an absent of lower sternum, ectopia cordis, midline abdominal skin defect, and omphalocele. b: The thorax/abdomen after surgery. c: Frontal facial view showing facial asymmetry, sparse hair, very deeply set eyes, bifid nose, midline cleft of upper lip, and irregular upper and lower vermillion. d: Side view of the face showing clefts running laterally towards external auditory canal, thin unfolded ears with detached trachus, bifid nose and midline cleft of upper lip.

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Figure 2. Limbs and caudal manifestation of Goltz–Gorlin syndrome in the present patient. a: Caudal appendage and areas with aplasia cutis on the back. b: Right hand: clefting of the hands, overlapping fingers and camptodactyly, thin nails. c: Left foot: small hallux, over-riding toes and bullous skin lesions. d: Right foot: split foot, underdeveloped hallux, complete syndactyly of second and third toes and fourth and fifth toes as well as bullous skin lesions.

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Echocardiography showed normal cardiac anatomy and presence of the pericardium. MRI of brain demonstrated colpocephaly and agenesis of corpus callosum. Ophthalmology exam showed bilateral complete anophthalmia. Hearing test documented unilateral hearing loss.

On the first day of life the chest and abdominal defect were surgically closed. During surgery it became clear the diaphragm showed a free sternal margin, allowing herniation of the bowels in the thorax, the cecum was not fixed, and there was no appendix. The sternal defect was not repaired. The postoperative course was uneventful. Follow-up showed a delayed psychomotor development and hypotonia but normal somatic growth.

CYTOGENETIC AND MOLECULAR ANALYSIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Chromosome analysis showed a normal, female karyotype (46, XX). MLPA failed to show subtelomeric imbalances, and a comparative genomic hybridization array did not detect any abnormalities either. PORCN was investigated by sequence analysis as described before [Maas et al., 2009], and disclosed the mutation c.727C>T. This single nucleotide substitution introduces a premature translation stop at amino acid Arginine 243 (p.Arg243X). The c.727C>T allele is predicted to produce a truncated protein and has been described twice before [Grzeschlik et al., 2007; Harmsen et al., 2009; Lombardi et al., submitted for publication].

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Goltz–Gorlin syndrome is an infrequently described congenital multisystem disorder with variable symptoms affecting tissues of ectodermal and mesodermal origin, and defined as a syndrome in 1962 by Robert W. Goltz and in 1963 by Robert J. Gorlin [Hennekam et al., 2010]. Goltz–Gorlin syndrome is an X-linked dominantly inherited disorder. Variability of the clinical phenotype has mainly been attributed to random X-chromosome inactivation. More than 90% of affected individuals are females. Affected males usually have a milder phenotype due to somatic mosaicism. Most cases are sporadic. In 2007, mutations were reported in PORCN at Xp11.23 [Grzeschlik et al., 2007; Wang et al., 2007]. Over 100 different PORCN mutations have been reported [Lombardi et al., submitted for publication; Bornholdt et al., 2009; Clements et al., 2009; Froyen et al., 2009].

The present patient shows the classical manifestations of Goltz–Gorlin syndrome, and the clinical diagnosis was molecularly confirmed. The c.727C>T (R243X) mutation has been reported twice before [Grzeschlik et al., 2007; Harmsen et al., 2009]. Grzeschlik et al. [2007] described a patient with classical Goltz–Gorlin syndrome, manifestations being linear skin lesion, syndactyly, asymmetric bone defects and dental defects. The phenotype in the patient with the R243X mutation described by Harmsen et al. [2009] had a severe, lethal phenotype: linear skin lesion, syndactyly of both hands and feet, malformed ears, iris coloboma, omphalocele, and hypoplastic left heart. The present patient has classical, severe Goltz–Gorlin syndrome and in addition four main signs of Cantrell (–Haller–Ravitsch) syndrome, which were absent in the earlier reported patients with the same mutation. There have been two patients who showed both Goltz–Gorlin syndrome and the pentalogy of Cantrell, molecularly confirmed. Maas et al. [2009] described two fetuses born to mothers with classical Goltz–Gorlin syndrome who had in addition the pentalogy of Cantrell including midline abdominal wall defects, sternum defects, anterior diaphragmatic defects, pericardial defects, and congenital heart anomalies. The mutations in these cases (c.947-2A>C and c.1344G>A) have not been reported by others. The authors also reported on an affected fetus with Goltz–Gorlin syndrome and a limb-body wall complex [Maas et al., 2009]. There have been other cases with manifestations of both entities that were not molecularly confirmed [van Allen et al., 1987; Samson and Viljoen 1995; Pivnick et al., 1998; Uygur et al., 2004].

The etiology and pathogenesis of the pentalogy of Cantrell is still unknown. Chromosome imbalances have been reported [Soper et al., 1986; Bick et al., 1988; Fox et al., 1988; Khoury et al., 1988; Hou et al., 2008]. Various etiological hypotheses have been put forward, such as an early amniotic sac rupture [Kaplan et al., 1985], amnion bands [Samson and Viljoen, 1995], a developmental field defect [Carmi and Boughman 1992; Martin et al., 1992; Korver et al., 2008], disturbance of mesoderm formation in very early embryonic life [Vazquez-Jimenez et al., 1998], and a vascular origin [Rashid and Muraskas, 2007]. Recurrence of the pentalogy of Cantrell has been reported in male siblings suggesting X-linked inheritance [Martin et al., 1992] and also in a mother and her two daughters representing a dominant condition [Forzano et al., 2005].

In patients with the pentalogy of Cantrell one or more signs of Goltz–Gorlin syndrome have been reported before. Limb anomalies may show resemblance to those in Goltz–Gorlin syndrome are the most common objects in patients with pentalogy of Cantrell [Samson and Viljoen, 1995; Pivnick et al., 1998; Uygur et al., 2004]. Sporadically, the eye abnormalities such as anophthalmia were reported [Samson and Viljoen, 1995]. Vazquez-Jimenez et al. [1998] analyzed 153 patients with the pentalogy of Cantrell from literature and found additional findings described in 28% of patients. These included central nervous system abnormalities (encephalocele, craniorachischisis, hydrocephaly); facial malformations (cleft lip/palate); gastrointestinal defects (gallbladder agenesis, liver disorders, malrotation); and limbs malformations (oligodactyly, absent tibia, absent radius, club foot).

It remains uncertain whether the combined phenotype Goltz–Gorlin syndrome–pentalogy of Cantrell can be explained by the nature or site of the PORCN mutation, or whether the phenotype is multifactorial determined by combined PORCN mutations with mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences. If sufficient samples of patients with both Goltz–Gorlin syndrome and the pentalogy of Cantrell are available it will be useful to perform next generation sequencing to check for mutations and polymorphisms in genes known to act within the Wnt pathway [Clements, 2009].

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

We are pleased to thank the parents of the here presented patient for their excellent cooperation.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. CYTOGENETIC AND MOLECULAR ANALYSIS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES