Route of delivery does not impact postnatal surgical morbidity in pregnancies affected by fetal achondroplasia.

PURPOSE: Pregnancies affected by maternal or fetal achondroplasia present unique challenges. The optimal route of delivery in fetuses with achondroplasia has not been established. Our objective was to determine whether the route of delivery affects postnatal achondroplasia-related surgical burden. METHODS: We conducted a secondary analysis of Achondroplasia Natural History Study (CLARITY), which is a multicenter natural history cohort study of patients with achondroplasia. Achondroplasia-related surgical morbidity, which we defined as the need for one or more postnatal achondroplasia-related surgeries, was assessed in relation to the route of delivery and whether the mother also had achondroplasia. Rate of each individual surgery type (otolaryngology, brain, foramen magnum, spine, and extremity) was also assessed in relation to the route of delivery. RESULTS: Eight hundred fifty-seven patients with achondroplasia with known route of delivery and known maternal stature were included. Three hundred sixty (42%) patients were delivered vaginally, and 497 (58%) patients were delivered by a cesarean delivery. There was no difference in the odds of requiring any postnatal achondroplasia-related surgery in those with achondroplasia who were delivered vaginally compared with those delivered by cesarean birth (odds ratio 0.95, 95% CI = 0.68-1.34, P = .80). No difference was present in the odds of requiring any postnatal achondroplasia-related surgery when route of delivery was compared for fetuses born to 761 average stature mothers (odds ratio 1.05, 95% CI = 0.74-1.51, P = .78). There was also no difference in the odds of requiring each of the individual achondroplasia-related surgeries by route of delivery, including cervicomedullary decompression. CONCLUSION: Our study suggests that it is reasonable for average stature patients carrying a fetus with achondroplasia to undergo a trial of labor in the absence of routine obstetric contraindications.

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.

Achondroplasia Natural History Study (CLARITY): a multicenter retrospective cohort study of achondroplasia in the United States.

PURPOSE: Achondroplasia is the most common short stature skeletal dysplasia (1:20,000-30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. METHODS: Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. RESULTS: Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values, 1,631 PSGs and 10,727 imaging studies. CONCLUSION: This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared.

CLARITY: Co-occurrences in achondroplasia-craniosynostosis, seizures, and decreased risk of diabetes mellitus.

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.

Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2.

We report three patients with Feingold 2 syndrome with the novel features of growth hormone deficiency associated with adenohypophyseal compression, aortic dilation, phalangeal joint contractures, memory, and sleep problems in addition to the typical features of microcephaly, brachymesophalangy, toe syndactyly, short stature, and cardiac anomalies. Microdeletions of chromosome 13q that include the MIR17HG gene were found in all three. One of the patients was treated successfully with growth hormone. In addition to expanding the phenotype of Feingold 2 syndrome, we suggest management of patients with Feingold 2 syndrome include echocardiography at the time of diagnosis in all patients and consideration of evaluation for growth hormone deficiency in patients with short stature.

Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia.

BACKGROUND: Skeletal dysplasia comprises a heterogeneous and collectively common group of inherited disorders of development, growth, and maintenance of the human skeleton. There is potential for increased perinatal morbidity and mortality in pregnant women who themselves have skeletal dysplasia, and for affected fetuses where skeletal dysplasia is suspected in utero. OBJECTIVE: We sought to establish guidelines for perinatal health care professionals who should be aware of these risks, to optimize maternal and child health pregnancy outcomes through best prenatal and delivery management practices. STUDY DESIGN: A panel of 13 multidisciplinary international experts participated in a Delphi process, which comprised consideration of thorough literature review and a list of 54 possible care recommendations subject to 2 rounds of anonymous voting and a face-to-face meeting. Those recommendations with >80% agreement were considered as consensual. RESULTS: During the first round, consensus was reached to support 30 out of the 54 statements. After the panel discussion, the group reached consensus on 40 statements. These statements include guidelines for the evaluation and treatment of pregnant women with skeletal dysplasia and for the unborn child with or suspected to have skeletal dysplasia. CONCLUSION: Consensus-based best practice guidelines are provided as a minimum of standard care to minimize associated health risks, and improve clinical outcomes for patients with skeletal dysplasia.

Best practices in peri-operative management of patients with skeletal dysplasias.

Patients with skeletal dysplasia frequently require surgery. This patient population has an increased risk for peri-operative complications related to the anatomy of their upper airway, abnormalities of tracheal-bronchial morphology and function; deformity of their chest wall; abnormal mobility of their upper cervical spine; and associated issues with general health and body habitus. Utilizing evidence analysis and expert opinion, this study aims to describe best practices regarding the peri-operative management of patients with skeletal dysplasia. A panel of 13 multidisciplinary international experts participated in a Delphi process that included a thorough literature review; a list of 22 possible care recommendations; two rounds of anonymous voting; and a face to face meeting. Those recommendations with more than 80% agreement were considered as consensual. Consensus was reached to support 19 recommendations for best pre-operative management of patients with skeletal dysplasia. These recommendations include pre-operative pulmonary, polysomnography; cardiac, and neurological evaluations; imaging of the cervical spine; and anesthetic management of patients with a difficult airway for intubation and extubation. The goals of this consensus based best practice guideline are to provide a minimum of standardized care, reduce perioperative complications, and improve clinical outcomes for patients with skeletal dysplasia.

Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

Factors associated with health-related quality of life (HRQOL) in adults with short stature skeletal dysplasias.

INTRODUCTION: Numerous factors associate with health disparities. The extent to which such factors influence health-related quality of life (HRQOL) among adults with short stature skeletal dysplasias (SD) is unknown. In an effort to update and clarify knowledge about the HRQOL of adults with SD, this study aimed to quantify HRQOL scores relative to the American average and assess whether specific indicators are associated with lower scores. METHODS: Members (>18 years) of Little People of America were invited to complete an online survey assessing HRQOL using the SF-12 supplemented with indicator-specific questions. SF-12 components (Physical Component Summary, PCS; Mental Component Summary, MCS) were compared to the standardized national American mean. Scores were divided at the median to identify factors associated with lower scores using multivariable logistic regression, adjusting for age, gender, race, education, and employment. RESULTS: A total of 189 surveys were completed. Mean and median PCS and MCS were below the national mean of 50 (p < 0.001). Advancing decade of age corresponded to a significant decline in PCS (p < 0.001) but not MCS (p = 0.366). Pain prevalence was high (79.4%); however, only 5.9% visited a pain specialist. Significant factors for lower PCS included age >40 years (p = 0.020), having spondyloepiphyseal dysplasia congenita (SED) or diastrophic dysplasia relative to achondroplasia (p = 0.023), pain (p < 0.001), and "partial" versus "full" health insurance coverage (p = 0.034). For MCS, significant factors included a lack of social support (p = 0.002) and being treated differently/feeling stigmatized by health care providers (p = 0.022). CONCLUSIONS: Individuals with SD face documented disparities and report lower HRQOL. Further research and interventions are needed to modify nuanced factors influencing these results and address the high prevalence of pain.

Characterization of complex chromosomal rearrangements by targeted capture and next-generation sequencing.

Translocations are a common class of chromosomal aberrations and can cause disease by physically disrupting genes or altering their regulatory environment. Some translocations, apparently balanced at the microscopic level, include deletions, duplications, insertions, or inversions at the molecular level. Traditionally, chromosomal rearrangements have been investigated with a conventional banded karyotype followed by arduous positional cloning projects. More recently, molecular cytogenetic approaches using fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), or whole-genome SNP genotyping together with molecular methods such as inverse PCR and quantitative PCR have allowed more precise evaluation of the breakpoints. These methods suffer, however, from being experimentally intensive and time-consuming and of less than single base pair resolution. Here we describe targeted breakpoint capture followed by next-generation sequencing (TBCS) as a new approach to the general problem of determining the precise structural characterization of translocation breakpoints and related chromosomal aberrations. We tested this approach in three patients with complex chromosomal translocations: The first had craniofacial abnormalities and an apparently balanced t(2;3)(p15;q12) translocation; the second has cleidocranial dysplasia (OMIM 119600) associated with a t(2;6)(q22;p12.3) translocation and a breakpoint in RUNX2 on chromosome 6p; and the third has acampomelic campomelic dysplasia (OMIM 114290) associated with a t(5;17)(q23.2;q24) translocation, with a breakpoint upstream of SOX9 on chromosome 17q. Preliminary studies indicated complex rearrangements in patients 1 and 3 with a total of 10 predicted breakpoints in the three patients. By using TBCS, we quickly and precisely defined eight of the 10 breakpoints.

Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene.

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.

The characterization of twenty sequenced human genomes.

We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.

Prevalence of Hearing Loss and Hearing Aid Use Among US Medicare Beneficiaries Aged 71 Years and Older.

Importance: National prevalence estimates are needed to guide and benchmark initiatives to address hearing loss. However, current estimates are not based on samples that include representation of the oldest old US individuals (ie, aged ≥80 years), who are most at-risk of having hearing loss. Objective: To estimate the prevalence of hearing loss and hearing aid use by age and demographic covariates in a large, nationally representative sample of adults aged 71 years and older. Design, Setting, and Participants: In this cohort study, prevalence estimates of hearing loss by age, gender, race and ethnicity, education, and income were computed using data from the 2021 National Health Aging and Trends Study. Survey weights were applied to produce nationally representative estimates to the US older population. Data were collected from June to November 2021 and were analyzed from November to December 2022. Main Outcomes and Measures: Criterion-standard audiometric measures of hearing loss and self-reported hearing aid use. Results: In this nationally representative sample of 2803 participants (weighted estimate, 33.1 million individuals) aged 71 years or older, 38.3% (95% CI, 35.5%-41.1%) were aged 71 to 74 years, 36.0% (95% CI, 33.1%-38.8%) were aged 75 to 79 years, 13.8% (95% CI, 12.6%-14.9%) were aged 80 to 84 years, 7.9% (95% CI, 7.2%-8.6%) were aged 85 to 89 years, and 4.0% (95% CI, 3.5%-4.6%) were aged 90 years or older; 53.5% (95% CI, 50.9%-56.1%) were female and 46.5% (95% CI, 43.9%-49.1%) were male; and 7.5% (95% CI, 6.2%-8.7%) were Black, 6.5% (95% CI, 4.4%-8.7%) were Hispanic, and 82.7% (95% CI, 79.7%-85.6%) were White. An estimated 65.3% of adults 71 years and older (weighted estimate, 21.5 million individuals) had at least some degree of hearing loss (mild, 37.0% [95% CI, 34.7%-39.4%]; moderate, 24.1% [95% CI, 21.9%-26.4%]; and severe, 4.2% [95% CI, 3.3%-5.3%]). The prevalence was higher among White, male, lower-income, and lower education attainment subpopulations and increased with age, such that 96.2% (95% CI, 93.9%-98.6%) of adults aged 90 years and older had hearing loss. Among those with hearing loss, only 29.2% (weighted estimate, 6.4 million individuals) used hearing aids, with lower estimates among Black and Hispanic individuals and low-income individuals. Conclusions and Relevance: These findings suggest that bilateral hearing loss is nearly ubiquitous among older US individuals, prevalence and severity increase with age, and hearing aid use is low. Deeper consideration of discrete severity measures of hearing loss in this population, rather than binary hearing loss terminology, is warranted.

Achondroplasia Natural History Study (CLARITY): 60-year experience with hydrocephalus in achondroplasia from four skeletal dysplasia centers.

OBJECTIVE: The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers. METHODS: The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information. RESULTS: A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of hydrocephalus at a median age of 14.4 months. There was considerable variation in the percentage of patients treated for hydrocephalus by center and decade of birth, ranging from 0% to 28%, although in the most recent decade, all centers treated less than 6% of their patients, with an average of 2.9% across all centers. Undergoing a cervicomedullary decompression (CMD) was a strong predictor for treatment of hydrocephalus (OR 5.8, 95% CI 3.9-8.4), although that association has disappeared in those born since 2010 (OR 1.1, 95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) has become more common; it was used as the first line of treatment in 38% of patients in the most recent decade. Kaplan-Meier analysis suggests that a single ETV will treat hydrocephalus in roughly half of these patients. CONCLUSIONS: While many children with achondroplasia have features of hydrocephalus with enlarged intracranial CSF spaces and relative macrocephaly, treatment of hydrocephalus in achondroplasia patients has become relatively uncommon in the last 20 years. Historically, there was a significant association between symptomatic foramen magnum stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor with the recognition that CMD alone will treat hydrocephalus in some patients. Despite good experimental data demonstrating that hydrocephalus in achondroplasia is best understood as communicating in nature, ETV appears to be reasonably successful in certain patients and should be considered an option in selected patients.

Otolaryngology Utilization in Patients With Achondroplasia: Results From the CLARITY Study.

OBJECTIVES/HYPOTHESIS: To quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi-specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization. RESULTS: In this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy-nine (56.7%) had tympanostomy tubes placed at least once, and 447 (32.5%) had tympanostomy tubes placed more than one time. Age at first pharyngeal surgery decreased by 1.2 years per birth cohort decade, and age at tympanostomy tube placement decreased by 1.1 years per decade. CONCLUSIONS: Patients with achondroplasia often require otolaryngologic surgery, particularly adenoidectomy and/or tonsillectomy as well as tympanostomy tube placement. Such surgery is performed now more frequently and at younger ages than in earlier decades. While otolaryngologic disease associated with achondroplasia is now recognized earlier and treated more frequently, long-term outcome studies are needed. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1548-1554, 2022.

Medicare Beneficiaries With Self-Reported Functional Hearing Difficulty Have Unmet Health Care Needs.

Hearing loss is associated with higher health care spending and use, but little is known about the unmet health care needs of people with hearing loss or difficulty. Analysis of 2016 Medicare Current Beneficiary Survey data for beneficiaries ages sixty-five and older reveals that those who reported a lot of trouble hearing in the past year were 49 percent more likely than those who reported no trouble hearing to indicate not having a usual source of care. Compared with those who reported no trouble hearing, those who reported some trouble hearing were more likely to indicate not having obtained medical care in the past year when they thought it was needed, as well as not filling a prescription, with the risk for both behaviors being greater among those reporting a lot of trouble hearing versus a little. Interventions that improve access to hearing services and aid communication may help older Medicare beneficiaries meet their health care needs.

Achondroplasia Natural History Study (CLARITY): 60-year experience in cervicomedullary decompression in achondroplasia from four skeletal dysplasia centers.

OBJECTIVE: The authors sought to determine the overall incidence of cervicomedullary decompression (CMD) in patients with achondroplasia and the characteristics associated with those surgeries across multiple institutions with experience caring for individuals with skeletal dysplasias. METHODS: Data from CLARITY (Achondroplasia Natural History Study) for 1374 patients with achondroplasia from four skeletal dysplasia centers (A. I. duPont Hospital for Children, Johns Hopkins University, University of Texas Health, and University of Wisconsin School of Medicine and Public Health) followed from 1957 to 2017 were recorded in a Research Electronic Data Capture (REDCap) database. Data collected and analyzed included surgeries, indications, complications, ages at time of procedures, screening procedures, and medical diagnoses. RESULTS: There were 314 CMD procedures in 281 patients (20.5% of the entire cohort). The median age of first CMD was 1.3 years in males and 1.1 years in females. Over time, there was a decrease in the median age of patients at first CMD. All patients born before 1980 who underwent CMD had the procedure after 5 years of age, whereas 98% of patients born after 2010 underwent CMD before 5 years of age. In addition, a greater proportion of patients born in more recent decades had documented neuroimaging and polysomnography (PSG) prior to CMD. Ventriculoperitoneal shunts (VPSs) were placed more frequently in patients undergoing CMD (23%) than in the entire cohort (8%). Patients who required either CMD or VPS were 7 times more likely to require both surgeries than patients who required neither surgery (OR 7.0, 95% CI 4.66-10.53; p < 0.0001). Overall, 10.3% of patients who underwent CMD required a subsequent CMD. CONCLUSIONS: The prevalence of CMD in this large achondroplasia cohort was 20%, with more recently treated patients undergoing first CMD at younger ages than earlier patients. The use of neuroimaging and PSG screening modalities increased over time, suggesting that increased and better surveillance contributed to earlier identification and intervention in patients with cervicomedullary stenosis and its complications.

Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study-a multi-center retrospective cohort study of achondroplasia in the US.

BACKGROUND: Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface retrusion, macrocephaly and a generalized spondylometaphyseal dysplasia which manifest as spinal cord compression, sleep disordered breathing, delayed motor skill acquisition and genu varus with musculoskeletal pain. To better understand the interactions and health outcomes of these potential complications, we embarked on a multi-center, natural history study entitled CLARITY (achondroplasia natural history study). One of the CLARITY objectives was to develop growth curves (length/height, weight, head circumference, weight-for-height) and corresponding reference tables of mean and standard deviations at 1 month increments from birth through 18 years for clinical use and research for achondroplasia patients. METHODS: All available retrospective anthropometry data including length/height, weight and head circumference from achondroplasia patients were collected at 4 US skeletal dysplasia centers (Johns Hopkins University, AI DuPont Hospital for Children, McGovern Medical School University of Texas Health, University of Wisconsin School of Medicine and Public Health). Weight-for-age values beyond 3 SD above the mean were excluded from the weight-for-height and weight-for-age curves to create a stricter tool for weight assessment in this population. RESULTS: Over 37,000 length/height, weight and head circumference measures from 1374 patients with achondroplasia from birth through 75 years of age were compiled in a REDCap database. Stature and weight data from birth through 18 years of age and head circumference from birth through 5 years of age were utilized to construct new length/height-for-age, weight-for-age, head circumference-for-age and weight-for-height curves. CONCLUSION: Achondroplasia-specific growth curves are essential for clinical care of growing infants and children with this condition. In an effort to provide prescriptive, rather than purely descriptive, references for weight in this population, extreme weight values were omitted from the weight-for-age and weight-for-height curves. This well-phenotyped cohort may be studied with other global achondroplasia populations (e.g. Europe, Argentina, Australia, Japan) to gain further insight into environmental or ethnic influences on growth.

Mapping the Relationship between Dysmorphology and Cognitive, Behavioral, and Developmental Outcomes in Children with Autism Spectrum Disorder.

Previous studies investigating the association between dysmorphology and cognitive, behavioral, and developmental outcomes among individuals with autism spectrum disorder (ASD) have been limited by the binary classification of dysmorphology and lack of comparison groups. We assessed the association using a continuous measure of dysmorphology severity (DS) in preschool children aged 2-5 years (322 with ASD and intellectual disability [ID], 188 with ASD without ID, and 371 without ASD from the general population [POP]). In bivariate analyses, an inverse association between DS and expressive language, receptive language, fine motor, and visual reception skills was observed in children with ASD and ID. An inverse association of DS with fine motor and visual reception skills, but not expressive language and receptive language, was found in children with ASD without ID. No associations were observed in POP children. These results persisted after exclusion of children with known genetic syndromes or major morphologic anomalies. Quantile regression models showed that the inverse relationships remained significant after adjustment for sex, race/ethnicity, maternal education, family income, study site, and preterm birth. DS was not associated with autistic traits or autism symptom severity, behaviors, or regression among children with ASD with or without ID. Thus, DS was associated with a global impairment of cognitive functioning in children with ASD and ID, but only with fine motor and visual reception deficits in children with ASD without ID. A better understanding is needed for mechanisms that explain the association between DS and cognitive impairment in children with different disorders. Autism Res 2020, 13: 1227-1238. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined whether having more dysmorphic features (DFs) was related to developmental problems among children with autism spectrum disorder (ASD) with or without intellectual disability (ID), and children without ASD from the general population (POP). Children with ASD and ID had more language, movement, and learning issues as the number of DFs increased. Children with ASD without ID had more movement and learning issues as the number of DFs increased. These relationships were not observed in the POP group. Implications are discussed.

Molecular (SNP) analyses of overlapping hemizygous deletions of 10q25.3 to 10qter in four patients: evidence for HMX2 and HMX3 as candidate genes in hearing and vestibular function.

We report on the analyses of four unrelated patients with de novo, overlapping, hemizygous deletions of the long arm of chromosome 10. These include two small terminal deletions (10q26.2 to 10qter), a larger terminal deletion (10q26.12 to 10qter), and an interstitial deletion (10q25.3q26.13). Single nucleotide polymorphism (SNP) studies (Illumina 550 K) established that these deletions resulted in the hemizygous loss of approximately 6.1, approximately 6.1, approximately 12.5, and approximately 7.0 Mb respectively. Additionally, these data establish that Patients 1, 2, and 3 share common, distal, hemizygous deleted regions of 6.09 Mb containing 37 RefSeq genes. Patients 3 and 4 share a 2.52 Mb deleted region corresponding to the proximal deleted region of Patient 3 and the distal deleted region of Patient 4. This common, hemizygous region contains 20 RefSeq genes including two H6 family homeobox genes (HMX2 and HMX3). Based on previous reports that Hmx2/Hmx3 knockout mice have vestibular anomalies, we propose that hemizygous deletions of HMX2 and HMX3 are responsible for the inner ear malformations observed from CT images, vestibular dysfunction, and congenital sensorineural hearing loss found in Patients 3 and 4.