Paul Kruszka

Down syndrome in diverse populations

Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P < 0.001, P < 0.001, P < 0.001, P < 0.05, and P < 0.05, respectively). Evaluation using a digital facial analysis technology of a larger diverse cohort of newborns to adults (n = 129 cases; n = 132 controls) was able to diagnose Down syndrome with a sensitivity of 0.961, specificity of 0.924, and accuracy of 0.943. Only the angles at medial canthus and ala of the nose were common significant findings amongst different ethnicities (Caucasians, Africans, and Asians) when compared to ethnically matched controls. The Asian group had the least number of significant digital facial biometrics at 4, compared to Caucasians at 8 and Africans at 7. In conclusion, this study displays the wide variety of findings across different geographic populations in Down syndrome and demonstrates the accuracy and promise of digital facial analysis technology in the diagnosis of Down syndrome internationally.

Renal growth in isolated methylmalonic acidemia

Purpose:We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia, a group of disorders associated with chronic kidney disease.Methods:Fifty patients with methylmalonic acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses.Results:Comparisons with age-matched controls showed that renal length in subjects with methylmalonic acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic acidemia cohort (P < 0.001; constant and slope).Conclusion:Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.Genet Med 15 12, 990–996.Genetics in Medicine (2013); 15 12, 990–996. doi:10.1038/gim.2013.42

22q11.2 deletion syndrome in diverse populations.

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.

Muenke syndrome: An international multicenter natural history study

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty‐five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x‐rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.

Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature.

Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras‐mitogen‐activated protein kinase (RAS‐MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month‐old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS‐MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS‐associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.

An electronic atlas of human malformation syndromes in diverse populations.

INTRODUCTION Birth defects remain a leading cause of infant mortality and childhood morbidity worldwide. As laboratory sequencing technologies become more available, recognition of malformation syndromes will become increasingly important. Most clinicians have been trained with clinical genetic resources that used patients of northern European descent as the standard of reference. The most well-known textbook of dysmorphology, Smith’s Recognizable Patterns of Human Malformation, shows predominantly Caucasian patients.1 Additionally, medical journals containing syndromes often show only patients of European ancestry. This poses a problem when confronted with patients from other parts of the world because of the wide range of normal physical features across the globe. As an example, many cases of Williams syndrome have been reported in the medical literature, but few reports involved African Americans or sub-Saharan Africans. Not surprisingly, the diagnostic criteria for Williams syndrome does not take into account differences in ethnicities.2 Thus, the diagnosis can be difficult in non-European patients, as exemplified by a report from subSaharan Africa where experienced geneticists struggled to diagnose Williams syndrome.3 Facing this obstacle, Shotelersuk published a book of syndromes of Thai individuals to provide ethnic-specific cases for physicians practicing in Thailand.4 This book and a recent commentary4,5 revealed the difficulty in diagnosing single-gene disorders in different ethnicities given the variation of phenotypes and appearances. A systematic collection of dysmorphologic disorders across patients of different ethnicities would be highly valuable for clinical diagnosis, providing genetic counseling, estimating population prevalence, and conducting research. We have had our own experiences in clinical genetics with challenges in identifying specific malformation syndromes in patients from different ethnicities. M.M. trained in pediatrics and genetics in Germany, where using textbooks with exclusive examples of photos of patients of northern European descent worked well, but later, while training at the Children’s Hospital of Philadelphia, he realized that he had to relearn morphologic features as they applied to diverse populations. A.A. trained in clinical genetics in Nigeria, using medical literature that did not adequately represent the syndromic features seen in subSaharan Africa, which inspired his first publication in morphology.6 P.K. has traveled and consulted in genetics throughout the world and has come to realize the importance of diagnostic tools for diverse populations that could be accessed on mobile devices. In this commentary, we introduce a freely available electronic photo atlas of individuals from diverse populations with human malformation syndromes. Photos for this website are previously unpublished and obtained from colleagues throughout the world. The core of this resource is a catalog of genetic and dysmorphologic syndromes with a molecular diagnosis, accompanied by photographs of affected patients of various ethnicities. This freely available clinical tool is located on the website for the National Human Genome Research Institute (NHGRI) (http://research.nhgri.nih.gov/ atlas). The atlas is searchable by phenotype, syndrome, ethnicity, and genetic/molecular diagnosis. To improve ease of access, the site will be optimized for mobile devices (such as smartphones and tablets), and an accompanying app will be developed. This resource will become increasingly important as congenital malformations comprise a larger fraction of childhood morbidity and mortality, with congenital abnormalities already ranking as the fifth leading cause of death in neonates (age 1–27 days) and accounting for 270,000 deaths worldwide in 2010 (4% of all deaths).7 With the rapid expansion of genetic and genomic medicine since completion of the Human Genome Project in 2003, Western countries have enjoyed these advances; however, in third-world countries where 80% of people live and 90% of births occur, there has been little impact.8 Genetic services have been traditionally available only at tertiary-care and university settings. In our expanding world, it is not possible for every individual with a genetic condition or a birth defect to have access to a clinical geneticist and a genetic counselor. Our tool will be well suited for use by both clinical geneticist and nongeneticist clinicians such as primary-care physicians, especially in developing countries. Making a proper and early syndromic diagnosis is paramount because late diagnosis can result in a delay in intervention and

Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome

Background Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated. Methods and results In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A (p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family. Conclusions Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2.

Expanding the phenotypic expression of Sonic Hedgehog mutations beyond holoprosencephaly.

oloprosencephaly (HPE) is the most common malformation of the human forebrain, occurring in approximately 1 in 250 gestations, although the birth prevalence falls to approximately 1 in 10,000 because of the high degree of intrauterine lethality. Holoprosencephaly results from failure or incomplete separation of the forebrain in early gestation and is categorized by the degree of forebrain separation into alobar (the most severe type), semilobar, lobar, middle interhemispheric variant, and septoproptic types. Microform HPE refers to a special category of HPE without neuroanatomic anomalies and neurocognitive disturbances, displaying midline anomalies on physical examination such as midface hypoplasia, hypotelorism, a flat or sharp nasal bridge, or a single maxillary central incisor but without the classic brain findings. Expanding efforts to characterize families with inherited forms of HPE have broadened the spectrum of the phenotype associated with mutations known to cause HPE. As described in the reported case, increasing numbers of family members carrying HPE mutations are being recognized with a microform presentation rather than the classic and severe HPE phenotype. In family members with microform signs, the mutation status may not be suspected until only after the recognition of a severely affected family member. The classic presentation of HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals, and developmental delay is present in almost all individuals. Other common problems include seizures and pituitary dysfunction. Most individuals studied with HPE have been children, including more than 600 patients in our laboratory, representing the largest single HPE sample set in the world. In children affected with HPE, morbidity and mortality are very common, with 50% of infants dying by 4 months of age and 90% are deceased by 1 year of age. The disorder is highly heterogeneous and includes a wide variety of teratogenic and genetic causes including large chromosomal imbalances, identifiable genetic syndromes such as Smith-Lemli-Opitz syndrome,

Noonan syndrome in diverse populations

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low‐set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.