Mutations in ASPH Cause Facial Dysmorphism,Lens Dislocation,Anterior-Segment Abnormalities,and Spontaneous Filtering Blebs,or Traboulsi Syndrome

We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl β-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development.     

46,XX/46,XX,del(20)(pter-->p12.2) mosaicism limited to fibroblasts associated with MCA/MR and severe growth deficit.

In this report the authors describe an 8-year-old severely mentally retarded girl with facial features resembling the facial dysmorphism seen in patients with Alagille-Watson syndrome, severe growth retardation and a 46,XX/46,XX,del(20)(pter-->p12.2) mosaicism in fibroblasts.     

Plain faces are more expressive: comparative study of facial colour,mobility and musculature in primates

Facial colour patterns and facial expressions are among the most important phenotypic traits that primates use during social interactions. While colour patterns provide information about the sender''s identity, expressions can communicate its behavioural intentions. Extrinsic factors, including social group size, have shaped the evolution of facial coloration and mobility, but intrinsic relationships and trade-offs likely operate in their evolution as well. We hypothesize that complex facial colour patterning could reduce how salient facial expressions appear to a receiver, and thus species with highly expressive faces would have evolved uniformly coloured faces. We test this hypothesis through a phylogenetic comparative study, and explore the underlying morphological factors of facial mobility. Supporting our hypothesis, we find that species with highly expressive faces have plain facial colour patterns. The number of facial muscles does not predict facial mobility; instead, species that are larger and have a larger facial nucleus have more expressive faces. This highlights a potential trade-off between facial mobility and colour patterning in primates and reveals complex relationships between facial features during primate evolution.     

One more case of a severe lethal condition resembling the Smith-Lemli-Opitz, type II syndrome.

A male child with a lethal multiple congenital anomaly syndrome of facial dysmorphism, ambiguous genitalia, syndactyly and postaxial polydactyly is presented. He had findings consistent with the diagnosis of Smith-Lemli-Opitz type II syndrome. Similar changes were observed in his elder sister, who died when she was 2 months old. On the basis of this familial observation the nosology of Smith-Lemli-Opitz syndrome is discussed.     

Cleft lip and/or palate in two cases of 46,X,i(Xq) Turner syndrome

Cleft lip (CL) and/or palate (CP) are uncommon anomalies in Turner syndrome (TS) series. We report two unrelated sporadic 46,X,i(Xq) patients exhibiting orofacial clefts and a peculiar facial appearance masking the clinical diagnosis. CL, and CP in case 1 and CP in case 2, though non-specific of TS, may not be fortuitous findings. The increased frequency of CP and bifid uvula in poly X syndromes, the dermatoglyphic similarities between iXq TS and X polysomies, and the occurrence of Klinefelter phenotype when extra Xq material is present in a male, are all indirect evidences suggesting that Xq material cannot be considered phenotipically inert and facial clefts found in our patients may be syndromal manifestation of trisomic Xq dosage.     

Upper labial deficiency in Mobius syndrome: a previously unreported feature and its correction

Bilateral facial palsy in M?bius syndrome remains one of the greatest challenges in reconstructive plastic surgery. Facial reanimation is an invaluable aid to such patients because it allows for greater social interaction by means of the ability to smile. In performing facial reanimation surgery on patients with M?bius syndrome, it is the observation of the senior author (Harrison) that upper labial deficiency is a consistent and previously unreported feature of the syndrome. It has been the practice of the senior author to perform upper labial augmentation on M?bius syndrome patients by insertion of a lipodermal autograft, in addition to facial reanimation. Nine patients with M?bius syndrome who presented to the Department of Plastic Surgery during an 8-year period were reviewed. All nine possessed bilateral facial palsy and upper labial deficiency in addition to other abnormalities consistent with M?bius syndrome. Six patients underwent bilateral facial reanimation and upper labial augmentation alone. One patient refused facial reanimation surgery but consented to upper labial augmentation. One patient, with concomitant micrognathia, underwent bilateral facial reanimation, upper labial augmentation, and insertion of a Silastic chin implant. In one patient, a child who also exhibited micrognathia, bilateral facial reanimation alone was carried out, with further procedures for upper labial and chin cosmesis being postponed until adulthood. The indication for performing upper labial augmentation was cosmetic. The procedure improved upper labial appearance and restored balance to the mouth. Patients also expressed higher satisfaction with eating and drinking, which they related to the improved fullness of the upper lip. This was before the facial reanimation had become functional. Upper labial deficiency warrants addition to the list of facial features of M?bius syndrome and is something that must be assessed in the context of facial reanimation surgery.     

A case of Melkersson-Rosenthal syndrome associated with Ehlers-Danlos syndrome

Melkersson-Rosenthal syndrome (MRS) is characterized by the triad of recurrent facial palsy, lingua plicata, and facial edema. Herein, we report a case of MRS associated with Ehlers-Danlos syndrome due to rare presentation. To the best of our knowledge only one case of MRS associated with Ehlers-Danlos syndrome has been reported in the literature until now.     

A second gene for autosomal dominant Möbius syndrome is localized to chromosome 10q, in a Dutch family.

Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial.     

A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features

The contiguous gene syndrome involving 8p11.2 is recognized as a combined phenotype of both Kallmann syndrome and hereditary spherocytosis, because the genes responsible for these 2 clinical entities, the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes, respectively, are located in this region within a distance of 3.2Mb. We identified a 3.7Mb deletion of 8p11.2 in a 19-month-old female patient with hereditary spherocytosis. The identified deletion included ANK1, but not FGFR1, which is consistent with the absence of any phenotype or laboratory findings of Kallmann syndrome. Compared with the previous studies, the deletion identified in this study was located on the proximal end of 8p, indicating a pure interstitial deletion of 8p11.21. This patient exhibited mild developmental delay and distinctive facial findings in addition to hereditary spherocytosis. Thus, some of the genes included in the deleted region would be related to these symptoms.     

Congenital facial palsy and emotion processing: The case of Moebius syndrome

According to the Darwinian perspective, facial expressions of emotions evolved to quickly communicate emotional states and would serve adaptive functions that promote social interactions. Embodied cognition theories suggest that we understand others' emotions by reproducing the perceived expression in our own facial musculature (facial mimicry) and the mere observation of a facial expression can evoke the corresponding emotion in the perceivers. Consequently, the inability to form facial expressions would affect the experience of emotional understanding. In this review, we aimed at providing account on the link between the lack of emotion production and the mechanisms of emotion processing. We address this issue by taking into account Moebius syndrome, a rare neurological disorder that primarily affects the muscles controlling facial expressions. Individuals with Moebius syndrome are born with facial paralysis and inability to form facial expressions. This makes them the ideal population to study whether facial mimicry is necessary for emotion understanding. Here, we discuss behavioral ambiguous/mixed results on emotion recognition deficits in Moebius syndrome suggesting the need to investigate further aspects of emotional processing such as the physiological responses associated with the emotional experience during developmental age.     

Allometry of facial mobility in anthropoid primates: implications for the evolution of facial expression

Body size may be an important factor influencing the evolution of facial expression in anthropoid primates due to allometric constraints on the perception of facial movements. Given this hypothesis, I tested the prediction that observed facial mobility is positively correlated with body size in a comparative sample of nonhuman anthropoids. Facial mobility, or the variety of facial movements a species can produce, was estimated using a novel application of the Facial Action Coding System (FACS). I used FACS to estimate facial mobility in 12 nonhuman anthropoid species, based on video recordings of facial activity in zoo animals. Body mass data were taken from the literature. I used phylogenetic generalized least squares (PGLS) to perform a multiple regression analysis with facial mobility as the dependent variable and two independent variables: log body mass and dummy-coded infraorder. Together, body mass and infraorder explain 92% of the variance in facial mobility. However, the partial effect of body mass is much stronger than for infraorder. The results of my study suggest that allometry is an important constraint on the evolution of facial mobility, which may limit the complexity of facial expression in smaller species. More work is needed to clarify the perceptual bases of this allometric pattern.     

Craniofacial morphology in the velo-cardio-facial syndrome

The velo -cardio-facial syndrome is a recently delineated congenital malformation syndrome, probably of autosomal dominant inheritance. Previous reports have concentrated on facial, oropharyngeal, cardiac, speech, language, and psychological features of this fairly common syndrome. To date, no radiographic data have been presented which might help to further delineate the syndrome, nor has there been an explanation of the characteristic facial appearance seen in this syndrome. This current study reports on cephalometric evidence of platybasia (obtuse angulation of the cranial base) in the velo -cardio-facial syndrome. The finding of platybasia adds one more phenotypic feature to the syndrome and also may help to explain the facial features of retrognathia, malar flatness, and prominence of the nasal root.     

A boy with classical Rubinstein-Taybi syndrome but no detectable mutation in the CREBBP and EP300 genes

Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant genetic disorder and is characterized by mental retardation, distinctive facial features, broad and often angulated thumbs and great toes. We report on a 7 year old boy with classical Rubinstein-Taybi syndrome. His facial and clinical features were very typical, including broad thumbs with radial angulation and broad great toes. Rigorous genetic analysis of the CREBBP and EP300 genes using DNA sequencing and multiple ligation-dependent probe amplification (MLPA) revealed no causative mutation in this boy, only a hitherto unreported but paternally inherited heterozygous sequence alteration, c.506 1+9C>T in IVS 30-31, which most likely represents a normal variant (NetGene 2 splice prediction software). We question if this boy could have a hitherto undetectable mutation type.     

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.     

Oculo-facio-cardio-dental syndrome in a girl and her mother

Congenital heart defects are known to be associated with facial dysmorphism and other congenital anomalies. Oculo-facio-cardio-dental (OFCD) syndrome is one such rare multiple congenital anomaly syndrome inherited as an X-linked dominant condition characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects and dental anomalies. It is unrecognized by many medical and dental professionals. Only 21 cases have been reported so far. This syndrome is often misrecognized as rubella embryopathy because of association of congenital cataract with cardiac anomalies. It is usually the orthodontists who diagnose the syndrome based on typical findings on dental panoramic radiographs. But we suspected our patient to be having OFCD syndrome based on typical facial dysmorphism, ocular and cardiac defects, and finally it was confirmed after noticing typical dental radiographic findings.     

Pure distal monosomy 10q26 in a patient displaying clinical features of Prader-Willi syndrome during infancy and distinct behavioural phenotype in adolescence

A male patient is reported with terminal 10q26 deletion and clinical findings suggesting Prader-Willi syndrome during the infancy. These findings included decreased fetal movements, neonatal hypotonia, need for tube feeding, characteristic facial dysmorphism with dolichocephaly, narrow bifrontal diameter, almond-shaped eyes and epicanthus, hypogenitalism and developmental retardation. However, during the further evolution there was neither hyperphagia nor obesity and chromosomal and molecular investigations failed to confirm the diagnosis of Prader-Willi syndrome. Special behavioural abnormalities became evident with notably hyperactivity, hyperkinesis and destructive tendency. Finally, at the age of 17 years high resolution chromosome studies revealed a terminal 10q26.3 deletion. A review of the literature is made on previously reported patients with either a Prader-Willi-like syndrome or a terminal 10q deletion with behavioural problems.     

A Novel PRKAR1A Mutation Associated With Primary Pigmented Nodular Adrenocortical Disease and the Carney Complex

ObjectiveTo delineate the genetic and phenotypic features of Carney complex in a family with multiple cases of primary pigmented nodular adrenocortical disease (PPNAD).MethodsDetailed clinical, laboratory, genetic, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed.ResultsA 17-year-old girl presented with symptoms and physical findings suggestive of hypercortisolemia, in addition to facial lentigines. She was found to have adrenocorticotropic hormone (ACTH)-independent Cushing syndrome. The adrenal glands appeared normal on computed tomographic scanning. Bilateral surgical adrenalectomy revealed PPNAD. Evaluation of her 14-year-old sister revealed ACTH-independent Cushing syndrome as well as facial lentigines, and adrenalectomy revealed PPNAD as well. Genetic testing of the 2 sisters and their mother (who also had multiple facial lentigines but did not have Cushing syndrome) revealed a novel mutation in the PRKAR1A gene.ConclusionWe describe a novel mutation in the PRKAR1A gene in a family with Carney complex and multiple members with PPNAD. PPNAD should be suspected in cases of ACTH-independent Cushing syndrome, and screening for Carney complex and its complications is recommended in all cases of PPNAD, including first-degree relatives. (Endocr Pract. 2010;16:198-204)