ABL1-related congenital heart defects and skeletal malformations syndrome in a patient from Sub-Saharan Africa: A case report highlighting novel cardiac features

Congenital heart defects and skeletal malformations syndrome (CHDSKM; OMIM #617602) is a rare syndrome characterized by distinctive facial features, congenital cardiac lesions, failure to thrive, and skeletal abnormalities. Hearing impairment, renal, and ophthalmological abnormalities have also recently been reported. We report here the clinical and molecular phenotype of an adolescent male who presented with multisystem involvement suggestive of a connective tissue disorder. The proband presented with the typical dysmorphic, skeletal, and skin findings of CHDSKM. In addition, he had several features not previously documented, including severe and rapidly progressive aortic root dilatation as well gastro-intestinal reflux secondary to esophageal dysmotility with gastric strictures. Genetic testing revealed a recurrent variant in the ABL1 gene, c.1066G>A, p.Ala356Thr. These novel features contribute to the growing body of knowledge regarding this rare and recently described condition as well as lend strength to previous calls for close surveillance of the aortic root from a young age in CHDSKM.     

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under‐diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African‐American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African‐American individuals with this syndrome, due to both altered frequencies of major anomalies and a non‐classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African‐American individuals. © 2011 Wiley‐Liss, Inc.     

Marshall-Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation

Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understanding the mechanism of comorbidities such as advanced bone age and aortic root dilatation in MRSHSS patients enables future development of anticipatory guidance, preventative care measures, and treatment guidelines.     

Aortic root dilatation in Ehlers-Danlos syndrome types I, II and III A report of five cases

We have identified five families in whom individuals affected with the Ehlers-Danlos syndrome (EDS) types I, II or III had aortic root dilatation (ARD). All propositi had a low upper/lower segment ratio but no other diagnostic skeletal or ocular features of Marfan syndrome. Their skin had the soft, velvety texture characteristic of EDS and all had significant joint laxity. Probands included a 4-year-old girl with EDS type I, 4-and 8-year-old girls with EDS type HI, a 35-year-old male with EDS type II, and a 51-year-old female with EDS type III. Review of these cases suggests the need for multicenter clinical studies in order to determine the prevalence and the rate of progression of ARD in EDS types I, II, and III. Such studies are necessary to determine whether echocardiograms (including measurement of aortic root diameter) should be considered on initial evaluation of all patients with mild forms of EDS.     

Auriculo-condylar syndrome is associated with highly variable ear and mandibular defects in multiple kindreds

We report on 20 individuals in 4 kindreds with auriculo-condylar syndrome (ACS), an autosomal dominant disorder characterized by congenital auricular clefts, mandibular condyle hypoplasia, temporomandibular joint (TMJ) abnormalities, micrognathia, microstomia, and a round facial appearance with prominent cheeks. Affected individuals have varying degrees of glossoptosis, respiratory distress, masticatory abnormalities, and malocclusion. Data from these families and those previously described suggest that this is a unique disorder with widely variable expression, including lack of obvious external anomalies in some individuals and severe ear malformations, condyle agenesis, and characteristic facial features in others. Early recognition of this condition should permit appropriate counseling and anticipatory guidance, including evaluation for reconstructive surgery and orthodontia and intervention for upper airway obstruction and sleep apnea.     

Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome

Radonic T, de Witte P, Groenink M, de Bruin‐Bon RACM, Timmermans J, Scholte AJH, van den Berg MP, Baars MJH, van Tintelen JP, Kempers M, Zwinderman AH, Mulder BJM. Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome. Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non‐progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z‐score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z‐score ≥2. Currently used Z‐scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re‐evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.     

Kabuki syndrome: description of dental findings in 8 patients

The cardinal features of Kabuki (Niikawa-Kuroki) syndrome (KS) include characteristic facial dysmorphic features, mild to moderate mental deficiency, skeletal abnormalities, dermatoglyphic abnormalities, and postnatal growth retardation. We identified 8 patients with KS in a genetics clinic over the past 5 years. All were Caucasians, except for 2 who were of mixed Aboriginal and Caucasian descent. All had the facial gestalt, the dermatoglyphic abnormalities characteristic of the syndrome, and developmental delay. Dental abnormalities of permanent teeth were seen in all 8 cases; 6 had missing lower incisors. Five patients had uniquely abnormal upper incisor teeth shape; the upper incisors had a 'flat head' screwdriver-shaped appearance. Other dental abnormalities included missing lower lateral incisors, missing second premolars, and ectopic upper 6-year molars. We believe the presence of the unique dental findings will prove useful in the diagnostic assessment of individuals with KS.     

Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller–Dieker syndrome

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller–Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.     

Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications

Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS-like disorders and suggest vascular imaging is indicated in these patients.     

TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature

You-Hoover-Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow-up data on four previously reported individuals with YHFS.     

Nablus syndrome: Easy to diagnose yet difficult to solve

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother–son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43–96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother–child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.     

Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome

Pitt-Hopkins syndrome (PHS) is characterized by severe mental retardation, characteristic facial features including a wide mouth and intermittent overbreathing. It is due to abnormalities of the TCF4 gene at 18q21.1 and over 50 cases have now been reported in the literature. The clinical features overlap significantly with those of Angelman, Rett, and Mowat-Wilson syndromes. We have observed prominent fetal pads as a feature in several individuals with PHS and suggested that this is a useful clinical sign which helps to distinguish PHS from other conditions in the differential diagnosis and may guide genetic testing.     

Hoffman syndrome: New patients, new insights

Hypogammaglobulinemia or agammaglobulinemia are major features of specific syndromes, including X-linked agammaglobulinemia and common variable immunodeficiency. However, the combination of hypogammaglobulinemia with specific dysmorphic features is less common, with only a few reported cases. One such report was a sporadic case of humoral immunodeficiency, facial dysmorphism, and limb anomalies in a young girl, later referred to as Hoffman syndrome. We report on a 7-year-old girl with almost complete loss of B cells, facial dysmorphism, and malformation of the limbs and genitalia, whose mother shows similar dysmorphic features with an attenuated version of the B-cell deficiency. We believe that all three cases described above represent the same condition. The features of the three affected individuals with Hoffman syndrome are reviewed. Further investigations in this recently recognized B-cell immunodeficiency syndrome are warranted.     

Clinical characteristics and rate of dilatation in Turner syndrome patients treated for aortic dilatation

Turner syndrome is associated with an increased risk of aortic aneurysms and dissection. Recent 2017 clinical care guidelines recommend medical therapy to treat aortic dilatation, although whether this slows dilatation is unknown. We aimed to describe a pre‐guideline cohort of Turner syndrome patients with aortic dilatation, the rate of dilatation following diagnosis, and post therapy dilatation rates. We conducted a retrospective review of Turner syndrome patients with a dilated aortic root or ascending aorta by current definitions. In total, 40 patients were included with 22 treated patients. Most patients had 45,X karyotype, were white, non‐Hispanic, and received both growth hormone and estrogen. Except for hypertension, there were no differences in risk factors among treated and untreated groups. Bicuspid aortic valve was very common. Treatment group patients had significantly more dilated ascending aortas by absolute measurements and aortic size index. In an adjusted model, there was minimal change in aortic measures over time and this was not associated with medication use. In conclusion, in this cohort, Turner syndrome patients with aortic dilatation were more likely to be treated if they had hypertension and if they met multiple dilatation criteria. Further study is needed to establish medical therapy efficacy on dilatation progression.     

Coloboma and other ophthalmologic anomalies in Kabuki syndrome: distinction from charge association

Kabuki (Niikawa-Kuroki) syndrome is associated with growth retardation, developmental delay, congenital heart disease, cleft palate, and characteristic facial features. Although the external appearance of the eyes has been well-described, the type and frequency of structural and functional eye anomalies has not been emphasized. We report three children with Kabuki syndrome who also had a retinal coloboma. A diagnosis of CHARGE association was initially suggested in two of the patients before the typical facial features of Kabuki syndrome emerged. A detailed review of reported cases of Kabuki syndrome shows that a variety of eye anomalies are associated with Kabuki syndrome. The incidence of coloboma is greatly increased in Kabuki syndrome. Thus, ophthalmologic abnormalities are frequently associated with Kabuki syndrome, and an ophthalmologic evaluation should be performed for each patient. Phenotypic overlap, including congenital heart, ear, and renal defects, can lead to the diagnosis of CHARGE association, especially since the typical facial features of Kabuki syndrome may not be apparent in early infancy. Thus, Kabuki syndrome should be considered in patients with coloboma if other features consistent with this condition are present, and follow-up evaluations are indicated for establishing the proper diagnosis.     

Craniofacial characteristics of fragile X syndrome in mouse and man

For a disorder as common as fragile X syndrome, the most common hereditary form of cognitive impairment, the facial features are relatively ill defined. An elongated face and prominent ears are the most commonly accepted dysmorphic hallmarks. We analysed 3D facial photographs of 51 males and 15 females with full FMR1 mutations and 9 females with a premutation using dense-surface modelling techniques and a new technique that forms a directed graph with normalized face shapes as nodes and edges linking those with closest dysmorphism. In addition to reconfirming known features, we confirmed the occurrence of some at an earlier age than previously recorded. We also identified as yet unrecorded facial characteristics such as reduced facial depth, hypoplasticity of the nasal bone–cartilage interface and narrow mid-facial width exaggerating ear prominence. As no consistent craniofacial abnormalities had been reported in animal models, we analysed micro-CT images of the fragile X mouse model. Results indicated altered dimensions in the mandible and both outer and inner skull, with the latter potentially reflecting differences in neuroanatomy. We extrapolated the mouse results to face shape differences of the human fragile X face.     

Fine-grained facial phenotype-genotype analysis in Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf-Hirschhorn syndrome facial phenotype.     

Hip displacement in Wolf–Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies

Wolf–Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf–Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.