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Keywords:

  • abdominal muscle hypoplasia;
  • anonychia;
  • central nervous system;
  • craniosynostosis;
  • differential diagnosis;
  • periventricular heterotopia

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Craniosynostosis is an etiologically heterogeneous malformation, which may present as an isolated finding or in association with other anomalies. The concurrence of craniosynostosis together with specific central nervous system, abdominal, genital, and limb malformations defines the Fontaine–Farriaux syndrome, described so far in only two patients. We report on a stillborn who mainly presented severe intrauterine growth retardation, bilateral coronal synostosis, generalized nail hypo/aplasia more evident on the posterior side, tapered digits, mild cutaneous syndactyly, abdominal muscle hypoplasia, micropenis and bilateral cryptorchidism. Skeletal radiographs revealed universal platyspondyly and necropsy findings comprised intestinal malrotation, abnormal cortical gyral formation, periventricular heterotopia, and cerebellar hypoplasia. Comparison between the present and the two previously described patients demonstrates that our case shows a combination of features strikingly resembling the original description. Conversely, the second reported patient shows a very atypical phenotype and is, most probably, affected by a distinct clinical entity. The triad of craniosynostosis, anonychia, and abdominal muscle hypo/aplasia emerges as the most consistent core phenotype, although skeletal and brain anomalies are relevant ancillary findings. An in-depth differential diagnosis with other partially overlapping conditions is carried out. © 2009 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

The term “craniosynostosis” refers to the process of premature fusion of the calvarial bones at the sutures. It may result in “craniostenosis”, which, in turn, describes the consequent abnormal head shape [Cohen, 2000a]. Craniosynostosis may present as an isolate form or in association with extracranial abnormalities, thus delineating recurrent malformation patterns. While the vast majority of patients with syndromic forms of craniosynostosis are affected by well-characterized clinical entities, a growing number of rarer conditions, reported in a few cases only, still await further delineation [Cohen, 2000b].

Fontaine et al. 1977 described a sporadic patient who died at 3.5 months and showed the unusual combination of synostotic brachycephaly, anonychia, abdominal muscle hypoplasia, and central nervous system anomalies. This condition was subsequently classified using the appellation of Fontaine–Farriaux syndrome (FFS) [Cohen, 1988]. A further patient was considered affected by the same clinical entity [Priolo et al., 2001]. Here, we report a male stillborn manifesting a constellation of features strikingly resembling FFS. We also compare our findings with collected data from the two previously described patients in order to better delineate this extremely rare syndrome.

CLINICAL REPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

The propositus was born to a 35-year-old Caucasian woman and her unrelated 37-year-old husband. Family history and physical examination of both parents were unremarkable. A previous pregnancy was complicated by extrauterine (tubaric) implantation and, then, was surgically treated. Serologic tests for toxoplasmosis, herpes viruses, rubella, and cytomegalovirus as well as triple serum marker screening were all negative. No exposure to any known or potential teratogenic agent was registered. Pregnancy evolved uneventful until the XXVIII gestation week, when an ultrasound scan revealed marked intrauterine growth retardation (IUGR), mild reduction of fetal movements, hyperechogenic bowel with generalized intestinal dilatation, and valgus deformity of the left great toe. A further ultrasound scan at XXIX gestation week confirmed previous anomalies and also demonstrated oligohydramnios without any evidence of placental dysfunction. Due to persistent IUGR, delivery was performed prematurely by cesarean at 32 weeks gestation. Birth weight was 866 g, length 36 cm, and head circumference 23 cm (all below the third centile, corrected for gestational age), and Apgar scores 31 and 45. At birth, the newborn presented cyanosis, marked hypotonia and severe respiratory distress, which requested intubation and immediate admission to the neonatal intensive care unit. The patient died 20 hr afterwards due to intractable cardio–respiratory failure.

Post-mortem physical examination revealed brachycephalic skull with increased interparietal diameter and marked reduction of the antero–posterior dimension, widened anterior fontanel, hypertelorism, underdevelopment of the middle third of the face with consequent malar hypoplasia and depressed periorbital region, short nose with broad base and anteverted nares, and low-set ears with flattened helix (Fig. 1A,B). Scalp hair presented an unusual distribution and was very sparse in both parietal areas (Fig. 1B). Digits of all four limbs were shortened and markedly tapered with nail hypo/aplasia. These abnormalities showed an antero–posterior gradient with more severe manifestations on the posterior side. Additional appendicular anomalies included mild bilateral cutaneous syndactyly between the III–IV and IV–V fingers, proximally placed V and great toes, tibial deviation of the II toes, and valgus deformity of the left hallux (Fig. 1C–E). Abdominal muscles were severely hypoplastic. In correspondence to the midline abdominal muscle defect the overlying skin was mildly redundant (Fig. 2A). In addition, there were micropenis, hypoplasia of the scrotum, and bilateral cryptorchidism (Fig. 2B). Subcutaneous fat was universally scarcely represented.

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Figure 1. Craniofacial and limb anomalies. Parietal bulging, hypertelorism, sunken eyes, and short nose with widened base and anteverted nares (a). Note paramedian notch of the upper lip (a). Reduced antero–posterior diameter of the cranial vault, malar hypoplasia, hypoplastic nasal bridge, low-set ear with flattened helix (b). Note the unusual distribution of the scalp hair, which are particularly sparse in the parietal area (b). Tapered fingers, anonychia of the III–V fingers, severe nail hypoplasia of the thumb and second finger, and mild cutaneous syndactyly between the III–IV and IV–V fingers (c). Left (d) and right (e) feet showing marked toe tapering more evident on the fibular side, anonychia of the III–V toes, hypoplastic nails of the great and II toes, distal tibial deviation of the II toes, hypoplasia of the V digits which are proximally placed. Also the great toes are slightly proximally placed. Note valgus deformity of the left great toe (d). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Figure 2. Abdominal and genital anomalies. Hypoplasia and severe diastasis of the abdominal muscles with mild redundancy of the skin (a). Micropenis without hypospadias, and hypoplasia of the scrotum with bilateral cryptorchidism (b). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Babygram showed synostotic brachycephaly due to bilateral premature fusion of the coronal sutures, increased interocular distance, upsweep of the orbitae with bilateral “harlequin” sign, hypoplasia of the malar bones and slight enlargement of the pituitary fossa (Fig. 3A,B). The spine revealed universal platyspondyly with multiple inferior and superior notching of the vertebral bodies (Fig. 3C). There was generalized distal phalanx hypo/aplasia, which was more marked on the posterior side of the upper and lower limbs (Fig. 3D).

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Figure 3. Skeletal findings. Brachycephalic skull with malar hypoplasia, upsweep of the orbitae, hypertelorism, and bilateral “harlequin” sign (arrows; a). Reduced anteroposterior diameter of the cranial vault, middle third facial hypoplasia, and slight enlargement of the pituitary fossa (b). Note relatively well-formed teeth (b). Lateral view of the lower thoracic and lumbar spine showing platyspondyly with superior and inferior notching of the vertebral body (c). X-ray of the left foot showing hypo/aplasia of the middle and distal phalanges more marked on the posterior side (d).

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On dissection, cranial vault demonstrated bilateral premature fusion of the coronal sutures (Fig. 4A). The brain surface showed gyral simplification, consistent with pachygyria, more evident on the anterior aspect of the frontal and temporal lobes (Fig. 4B,C). In addition, there was cerebellar hypoplasia without growth discrepancy between hemispheres and vermis (Fig. 4B). Microscopic examination revealed abnormal persistence of neurons in the periventricular region. These neurons, which were dysplastic, formed a thick layer all along the lateral ventricle walls and sometimes constituted nodules (Fig. 4D). These features were indicative of subependymal heterotopia and were easily differentiated from a normal periventricular germinal matrix. Basal ganglia were not well identified with lack of their proper cytoarchitectonic features and were substituted by irregular clusters of neurons. The multilayer organization of the cortical gray matter was grossly conserved, although there was focal neuronal paucity more evident in the parietal lobes. Necropsy confirmed severe abdominal muscle hypoplasia and also revealed partial malrotation of the gut with lack of fixation of the cecum, right and transverse colon, bowel dilatation with a thinned wall, and multiple volvuli. Heart and lungs were morphologically unremarkable, except for diffuse pulmonary edema, which was interpreted as the cause of death. Urinary bladder was distended with a grossly normal microscopic appearance of the bladder wall and absence of any structural anomaly of the urethra, ureters, and kidneys. Both testes were located in the abdominal cavity and had a normal microscopic appearance.

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Figure 4. Pathological findings. Cranial base after brain dissection showing bilateral premature fusion of the coronal sutures, and severe diastasis of the metopic and sagittal sutures (a). Pachygyria more evident on the frontal and temporal lobes (b). The cerebellum appears significantly hypoplastic in comparison with the prosencephalon (b). Gross coronal section of the brain showing gyral simplification (c). Photomicrograph from the periventricular region (hematoxylin and eosin staining; original magnification 40x) demonstrates heterotopic neurons forming thick clusters of cells, which sometimes assume a nodular aspect (arrow; d). The lateral ventricle cavity is marked by an asterisk (d). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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A 450-band level karyotype on cultured fibroblasts was normal male. Subtelomeric rearrangements were excluded by multiplex ligation-dependent probe amplification (MLPA) analysis using SALSA MLPA kit P070 (MRC Holland, Amsterdam/Netherlands). In order to investigate further genomic rearrangements we also performed a CGH-Array analysis using the Agilent Human Genome CGH Microarray 44K (43 KB overall median probe spatial resolution and 24 KB median probe spacing in Refseq genes). Statistical analysis has been performed by CHHweb with a cutoff threshold equal to 0.2 [Lai et al., 2008]. The CGH analysis did not find any statistical significant aberrant region. Finally, due to the concurrence of craniosynostosis and severe limb defects, direct sequencing of exon 7 of FGFR1, exons 3, 5, 8, 10, 11, 14–17 of FGFR2, and exons 7 and 10 of FGFR3 was performed and failed to identify any pathogenic change.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Our patient shows a peculiar malformation pattern chiefly characterized by bilateral coronal synostosis with consequent hypoplasia of the middle third of the face, abnormal cortical gyral formation, periventricular heterotopia, hypo/aplastic phalanges and nails with more severe manifestation on the posterior side, mild cutaneous syndactyly, abdominal muscle hypo/aplasia, intestinal malrotation, hypogenitalism, severe growth deficiency and early lethality. A strikingly similar concurrence of features was first described by Fontaine et al. 1977. The diagnosis of FFS was subsequently proposed in a further patient, presenting with pansynostosis, periventricular heterotopia, minor limb anomalies, congenital heart defect, pyloric stenosis, hypospadias, and postnatal growth delay [Priolo et al., 2001]. Comparison among our and the two previously described patients with suspected FFS is summarized in Table I. Based on literature data, while the present and original cases display overlapping features, the patient by Priolo et al. 2001 manifests a quite distinct phenotype, lacking anonychia, abdominal wall deficiency, abnormal cortical development and early lethality. Thus, it seems more prudent to consider the case by Priolo et al. 2001 affected by a different clinical entity. Alternatively, the phenotype observed in our and original patients could represent the severe end of a wider spectrum, which may include milder manifestations, such as the case by Priolo et al. 2001. In this setting, two previously described patients presenting with growth delay of prenatal onset, generalized lipoatrophy, wrinkled skin, brachycephaly, nail hypo/aplasia, large umbilical hernia and spine malformations [Petty et al., 1990], show a phenotype strikingly resembling FFS. However, this hypothesis, at the moment, remains unconfirmed due to the lack of details about cranial suture and central nervous system anomalies.

Table I. Previously Published and Present Patients With Fontaine–Farriaux Syndrome
FeaturePresent caseFontaine et al. 1977Priolo et al. 2001
  1. ASD, atrial septal defect; IUGR, intrauterine growth retardation; n.a., not available; SP, stenosis of the left pulmonary artery; VSD, ventricular septal defect.

SexMaleMaleMale
Oligohydramnios+
Severe IUGR++
Postnatal growth delayn.a.++
Adipose tissue anomaliesHypoplasia of the subcutaneous fatPatchy lipodystrophyGeneralized lipoatrophy
Head shapeBrachycephalyBrachycephalyScaphocephaly
CraniosynostosisBilateral coronalBilateral coronalSagittal, partial coronal and lambdoid
Triangular face+++
Shallow orbits+++
Depressed nasal bridge+++
Low-set ears++
Abnormal scalp hair pattern++
Gyral simplification++
Thin corpus callosum+
Periventricular heterotopia+n.a.+
Disorganization of the basal ganglia++n.a
Hypoplastic cerebellum++
Anonichia++
Fetal fingerpads+
Distal phalanx hypo/aplasia+++
Cutaneous syndactyly+++
Congenital heart diseaseVSDASD, SP
Cleft vertebrae+
Platyspondyly++
Abdominal muscle hypo/aplasia++
Intestinal malrotation++
Pyloric stenosis+
Hypospadias/micropenis+++
Cryptorchidism++
OutcomePerinatal deathDead at 3.5 monthsAlive at 5 months

In addition to craniosynostosis, the concurrence of such a broad spectrum of extracephalic anomalies considerably limits the differential diagnosis. Gyral abnormalities and neuronal heterotopias, observed in both FFS patients, are an overall uncommon finding in craniosynostosis syndromes, although they have been occasionally reported in several and well-defined conditions, such as Apert, Pfeiffer and Saethre–Chotzen syndromes, as well as the thanatophoric dysplasias [Camfield et al., 2000; Raybaud and Di Rocco, 2007]. Therefore, this association seems to have not a consistent diagnostic value in FFS. On the other hand, to our knowledge, anonychia was reported only in two further extremely rare craniosynostosis syndromes, namely Genoa and Gorlin–Chaudhry–Moss syndromes [Ippel et al., 1992; Lapunzina et al., 2001]. However, they may be easily distinguished from FFS by the occurrence of holoprosencephaly and peculiar facial gestalt, respectively. Two families presenting distal symphalangism variably associated with absent nails, craniosynostosis and additional minor skeletal findings, were also described [Ventruto et al., 1976; Poush, 1991]. Nevertheless, in both pedigrees the clinical picture is very mild, being inherited as an autosomal dominant trait, and only occasionally characterized by the concurrence of cranial vault and nail anomalies. A further unusual combination of features observed in FFS is the dyad of craniosynostosis and abdominal muscle hypo/aplasia. Both features have been previously described in three cases of Pfeiffer syndrome type II or III [Bracero et al., 1988; Barone et al., 1993], which, in turn, could be easily excluded in our patient by the overall different appendicular anomalies and negative FGFRs molecular screening. Of note, an indirect evidence of abdominal muscle deficiency is observed in Carpenter syndrome, in which umbilical hernia is a relatively common finding [Jenkins et al., 2007]. Table II illustrates differential diagnosis among FFS and other partially overlapping craniosynostosis syndromes. Finally, absent nails due to distal phalangeal hypo/aplasia is a rare dysmorphic feature, which may be observed in a few conditions, such as Yunis–Varon, DOOR and Zimmermann–Laband syndrome [Chadwick et al., 1994; James et al., 2007; Basel-Vanagaite et al., 2008]. However, they display a constellation of additional findings, which make straightforward the differential diagnosis.

Table II. Differential Diagnosis of Fontaine–Farriaux Syndrome and Other Partially Overlapping Conditions
CharacteristicFontaine–Farriaux syndromeGorlin–Chaudhry–Moss syndromePfeiffer syndrome type II and IIICarpenter syndromeGenoa syndromeVentruto et al. 1976
  1. n.a., not available; +, common feature; +/−, occasional feature; −, never reported feature.

Predominant cranial shapeAcro/brachycephalyAcrocephalyCloverleaf skull or brachycephalyAcrocephalyPlagiocephalyBrachycephaly (?)
Gyral anomalies++/−
Holoprosencephaly+
Hydrocephalus+++
Cerebellar anomalies++/−
Microphthalmia++
Hearing lossn.a.++/−
Tooth anomaliesn.a.++
Cleft palate/high arched palate++++
Congenital heart defect+/−++
Platyspondyly+
Abdominal muscle hypoplasia++/− (umbilical hernias)+/−+ (umbilical hernias)
Intestinal malrotation++/−
Abnormal genitalia+++
Nail hypo/aplasia++++
Distal phalangeal hypoplasia++++
Syndactyly+++
Polydactyly+
Broad thumb/hallux+
Synphalangism/carpal-tarsal fusions+
Elbow joint limitation+
Hip dysplasia+
Adipose tissue hypoplasia+
Obesityn.a.+
Hypertrichosisn.a.+
Growth delay+++
Early lethality+++/−

Overall, the triad of craniostenosis, anonychia, and extensive abdominal muscle hypoplasia emerges as a quite specific combination of features in FFS. In fact, to our knowledge, not any other human malformation syndrome consistently presents this combination of anomalies. In theory, these three features could coexist in fetal cocaine syndrome [Winter and Baraitser, 2005]. However, in this still debated clinical entity, premature fusion of the cranial sutures is always secondary to impaired brain growth and absence of nails is usually part of more severe transverse limb defects. Further reports are expected in order to confirm this preliminary evidence and to better delineate this apparently rare phenotype.

Very little is known about the etiology of FFS. Our patient and that by Fontaine et al. 1977 are sporadic and born from healthy non-consanguineous parents. There is not convincing evidence of advanced parental age at conception and teratogen exposure. Due to the (apparent) extreme rarity of the condition, the absence of affected females is, at the moment, a weak support for an X-linked mutation. Standard and molecular cytogenetic studies performed in our patient make very unlikely the presence of a criptic chromosome rearrangement. Given the concurrence of craniosynostosis and hand/foot anomalies reminiscent of brachydactyly type B [Oldridge et al., 2000], the FFS causative gene or exogen agent should display pleiotropic effects on different morphogenetic patterns, including cranial suture formation and limb proximal–distal patterning. In our patient, molecular screening excluded any known FGFR1-3 mutation. Nevertheless, some evidences indicate that also their ligands, such as FGF4, have a role in both processes [Mathijssen et al., 2001; Mariani et al., 2008] and suggest that they might be implicated in human malformations [Jehee et al., 2007]. Very recently, mutations in RAB23, coding for a negative regulator of the sonic hedgeohog signalling, are identified in Carpenter syndrome, which shares with FFS craniosynostosis and, possibly, abdominal muscle deficiency [Jenkins et al., 2007]. This implies that perturbations of this pathway might be involved in the etiopathogenesis of other craniosynostosis syndromes, including FFS.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

The authors wish to thank Mrs. Paola Menichetti (Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy) for kind assistance in the bibliographic search.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Editor's Note In this article by Castori et al., the authors describe a stillborn infant with the Fontaine-Farriaux syndrome. In the ensuing paper, Delgado et al. report on a boy with what the authors consider to be the third case of the Petty-Laxova-Wiedemann syndrome. Both authors raise the issue as to whether these two entities might represent the same disorder. Individuals called Fontaine-Farriaux syndrome have been infants, while those with the Petty-Laxova-Wiedemann were older individuals when described. Additional reports will be needed to resolve the question. Despite that issue, these two papers help delineate the phenotypes of the two named disorders. John C. Carey

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