Distinctive Craniofacial Features Research Articles

Avoid overstepping the bounds of evidence: the role of the orthodontist in managing pediatric Obstructive Sleep Apnea

IntroductionPediatric Obstructive Sleep Apnea (OSA) is a common sleep-related breathing disorder often linked to distinct craniofacial features and malocclusions. While orthodontic treatments, particularly maxillary expansion and mandibular advancement, have been suggested for managing this condition, the results remain controversial and are based on low-quality evidence. This paper aims to summarize the ongoing debates on this topic by reviewing relevant literature and highlighting the role of the orthodontist in diagnosing and managing OSA in daily clinical practice.Discussion and conclusionsAccording to the present review, there is insufficient evidence to either confirm or deny the effectiveness of oral appliances for treating pediatric OSA due to significant methodological limitations, such as small sample sizes, inadequate control groups, short study durations, and a lack of long-term follow-up. Additionally, this condition cannot be diagnosed solely based on craniofacial morphology, but an interdisciplinary evaluation is strictly required. In addition, orthopedic treatment may be considered only as an adjunct therapy for children with craniofacial anomalies increasing the risk for OSA, and the combination of multiple therapeutic approaches may be necessary to achieve effective treatment outcomes.

New Insights Into the Spectrum of RASopathies: Clinical and Genetic Data in a Cohort of 121 Spanish Patients.

Noonan syndrome and related disorders are a group of well-known genetic conditions caused by dysregulation of the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway. Because of the overlap of clinical and molecular features, they are now called RASopathies. In this study, we retrospectively analyzed the clinical data of 121 patients with a molecularly confirmed diagnosis of RASopathy, describing frequencies for clinical features in all organ systems as well as molecular data. The most common clinical diagnosis was Noonan Syndrome and the most frequently affected gene was PTPN11 followed by SOS1, RAF1, LZTR1, and RIT1. All patients had distinctive craniofacial features indicative of the RASopathy spectrum but we report some atypical features regarding craniofacial shape, such as craniosynostosis and microcephaly. We also describe uncommon clinical characteristics such as aortic dilation, multivalvular heart disease, abnormalities of the posterior fossa, and uterine congenital anomalies in female patients. Furthermore, the presence of multiple giant cell granulomas was observed specifically in patients with SOS1 variants. This comprehensive evaluation allows broadening the phenotypic spectrum of our population and their correlation with the genotype, which are essential to improve the recognition and the follow up of RASopathies as a multisystemic disease.

6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity

Abstract Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None. Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal >7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C>A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency. Presentation: 6/3/2024

RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model

Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb–1.5 Mb microdeletions that include RFC2, as well as one patient with a 167 kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate a KO zebrafish of its paralog gene, rfc5, to better understand the functions of these RFC genes in development and disease. Both rfc2 and rfc5 KO zebrafish exhibit similar phenotypes reminiscent of WS, including small head and brain, jaw and dental defects, and vascular problems. RNA-seq analysis reveals that genes associated with neural cell survival and differentiation are specifically affected in rfc2 KO zebrafish. In addition, heterozygous rfc2 KO adult zebrafish demonstrate an anxiety-like behavior with increased social cohesion. These results suggest that RFC2 may contribute to the pathogenicity of Williams syndrome, as evidenced by the zebrafish model.

Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report

BackgroundRing chromosome 14 syndrome is a rare disorder primarily marked by early-onset epilepsy, microcephaly, distinctive craniofacial features, hypotonia, intellectual disability, and delay in both development and language acquisition.Case presentationA 21-year-old woman with a history of epileptic seizures since the age of 1.5 years presented with distinctive craniofacial features, including a prominent and narrow forehead, sparse and short eyebrows, palpebral ptosis, horizontal palpebral fissures, a broad nasal bridge, a prominent nasal tip, a flat philtrum, hypertelorism, midfacial hypoplasia, horizontal labial fissures, a thin upper lip, crowded teeth, an ogival palate, retrognathia, and a wide neck. Additional physical abnormalities included kyphosis, lumbar scoliosis, pectus carinatum, cubitus valgus, thenar and hypothenar hypoplasia, bilateral hallux valgus, shortening of the Achilles tendon on the left foot, and hypoplasia of the labia minora. Chromosomal analysis identified a ring 14 chromosome with breakpoints in p11 and q32.33. An aCGH study revealed a ~ 1.7 Mb deletion on chromosome 14qter, encompassing 23 genes. Genomic instability was evidenced by the presence of micronuclei and aneuploidies involving the ring and other chromosomes.ConclusionThe clinical features of our patient closely resembled those observed in other individuals with ring chromosome 14 syndrome. The most important point was that we were able to verify an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus.

Cornelia de Lange Spectrum

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis.Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved.Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early.

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.

“Liu-Liang-Chung” syndrome with multiple congenital anomalies and the distinctive craniofacial features caused by dominant ZEB2 gene gain mutation

BackgroundContiguous gene gain syndrome including entire ZEB2 may be a novel syndrome. In the past, there were no easily distinct and recognizable features as a guide for precise clinical and genetic diagnosis of the syndrome.Case presentationWe report a novel case with the syndrome with a novel de novo 22.16 Mb duplication at 2q21.2-q24.1. The syndrome is characterized by multiple anomalies including the same typical craniofacial phenotype that is entirely different from Mowat–Wilson syndrome (MWS), and other quite similar features of MWS consisting of development delay, congenital heart disease, abdominal abnormalities, urogenital abnormalities, behavioral problems and so on, in which the distinctive craniofacial features can be more easily recognized.ConclusionsContiguous gene gain syndrome including entire ZEB2 characterized with similar multiple congenital anomalies of MWS and the distinctive craniofacial features is mainly caused by large 2q22 repeats including ZEB2 leading to dominant singe ZEB2 gene gain mutation, which is recommended to be named “Liu-Liang-Chung” syndrome. We diagnose this novel syndrome to distinguish it from MWS. Some variable additional features in the syndrome including remarkable growth and development retardation and protruding ears were recognized for the first time.

Orthodontic Management of Severe Hypodontia and Impacted Maxillary Second Molars in a Patient with Sotos Syndrome.

Sotos syndrome is a genetic disorder characterized by distinct craniofacial features, overgrowth in childhood, and impaired intellectual development. We herein report the successful orthodontic treatment of a 14-year-old boy with Sotos syndrome caused by a heterozygous mutation in the NSD1 gene. He showed severe hypodontia, impaction of the maxillary second molars and a skeletal Class III jaw-base relationship. Orthodontic management, including space control by protraction of the maxillary first molars and traction of the impacted molars, was performed using fixed appliances and miniscrews. As a result, acceptable occlusion was obtained without any discernible relapse 18 months postretention.

Hominin fossils from Kromdraai and Drimolen inform Paranthropus robustus craniofacial ontogeny

Ontogeny provides critical information about the evolutionary history of early hominin adult morphology. We describe fossils from the southern African sites of Kromdraai and Drimolen that provide insights into early craniofacial development in the Pleistocene robust australopith Paranthropus robustus. We show that while most distinctive robust craniofacial features appear relatively late in ontogeny, a few do not. We also find unexpected evidence of independence in the growth of the premaxillary and maxillary regions. Differential growth results in a proportionately larger and more postero-inferiorly rotated cerebral fossa in P. robustus infants than in the developmentally older Australopithecus africanus juvenile from Taung. The accumulated evidence from these fossils suggests that the iconic SK 54 juvenile calvaria is more likely early Homo than Paranthropus. It is also consistent with the hypothesis that P. robustus is more closely related to Homo than to A. africanus.

Craniofacial Morphology of Temporomandibular Disorder Patients with Different Disc Positions: Stratifying Features Based on Sex and Sagittal Skeletal Pattern.

Disc displacement (DD) appears in the majority of temporomandibular disorder (TMD) patients. The correlation between craniofacial morphology and different disc positions has been underlined, while the craniofacial morphological differences based on sex and sagittal skeletal pattern stratification have been insufficiently studied. In this study, 304 patients with TMD complaints were included and classified into normal position, disc displacement with reduction (DDwR) and disc displacement without reduction (DDwoR) groups according to magnetic resonance imaging. A total of 24 cephalometric measurements, covering the cranial base, vertical relationship, sagittal relationship, mandible position and morphology, and dental relationship, were assessed using lateral cephalograms. A stratified analysis was performed based on the sex and sagittal skeletal pattern. Overall, DD patients had distinctive craniofacial morphological features. The posterior cranial base length and mandibular arc angle were statistically different only in females, while the Y-axis angle, occlusal plane angle and sella nasion point A angle (SNA) might be unique features in males. Skeletal class II had the most statistically different measurements compared to the others. Differences in the Frankfort mandibular incisor angle (FMIA) and saddle angle were especially displayed in skeletal class III patients. The sex and skeletal sagittal pattern could affect the morphological differences in TMD patients with different disc positions.

Baz1b loss-of-function in zebrafish produces phenotypic alterations consistent with the domestication syndrome

BAZ1B is a ubiquitously expressed nuclear protein with roles in chromatin remodeling, DNA replication and repair, and transcription. Reduced BAZ1B expression disrupts neuronal and neural crest development. Variation in the activity of BAZ1B has been proposed to underly morphological and behavioral aspects of domestication through disruption of neural crest development. Knockdown ofbaz1b in Xenopus embryos and Baz1b loss-of-function (LoF) in mice leads to craniofacial defects consistent with this hypothesis. We generated baz1b LoF zebrafish using CRISPR/Cas9 gene editing to test the hypothesis that baz1b regulates behavioral phenotypes associated with domestication in addition to craniofacial features. Zebrafish with baz1b LoF show mild underdevelopment at larval stages and distinctive craniofacial features later in life. Mutant zebrafish show reduced anxiety-associated phenotypes and an altered ontogeny of social behaviors. Thus, in zebrafish, developmental deficits in baz1b recapitulate both morphological and behavioral phenotypes associated with the domestication syndrome in other species.

A 15-Year-Old Girl with Trichorhinophalangeal Syndrome Type 1 with Non-ossifying Fibroma in Femur: A Case Report

Introduction: Trichorhinophalangeal syndrome (TRPS) is a sporadic autosomal dominant disorder with approximately 200 reported cases worldwide. We aimed to report a 15-year-old girl with TRPS type 1 (TRPS1) and the second reported case with a rare non-ossifying fibroma (NOF) in the distal part of her left femur. Case Presentation: We introduce a 15-year-old girl who presented to the outpatient rheumatology clinic at 17 Shahrivar Children's Hospital, Rasht, Iran, with the chief complaint of osteoarticular pain and bone deformities. She had sparse hair, a recession of the fronto-temporal hairline, and unusually thick eyebrows at the medial and abnormal sparseness of the lateral margins. Physical examination of the limbs revealed short fingers and toes with proximal interphalangeal (PIP) ulnar deviation of the second and third fingers in both hands. Shortness of the fourth fingers, especially in the right hand, and the swelling of the PIP joints of both hands were prominent. Genetic analysis showed deletion mutation in the TRPS1 gene in chromosome 8q24 compatible with TRPS1. Conclusions: Several symptoms and signs, including distinctive craniofacial features and ectodermal and skeletal abnormalities, are used for proper TRPS diagnosis. A correct and on-time diagnosis is essential to perform supportive care for the patient to prevent morbidities. Bone lesions, such as NOF1, can also be presented in TRPS1 patients and may be correlated with TRPS1 mutation. Further investigations are required on the association of the TRPS gene with NOF bone lesions.

Exome and RNA-Seq analyses of an incomplete penetrance variant in USP9X in female-specific syndromic intellectual disability.

Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features. We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, X-inactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.

EP200: Noonan syndrome associated with focal occipital alopecia in a patient with RAF1 variant: A case report and literature review

Noonan syndrome (NS) is a heterogenous condition characterized by distinctive craniofacial features, cardiac defects, and neurodevelopmental changes and is caused by variants in one of seven genes coding for proteins within the Ras-MAPK pathway. Pathogenic variants in RAF1 account for approximately 3-17% of cases and are associated with a high prevalence of severe hypertrophic cardiomyopathy (HCM) and pulmonary hypertension (PHTN). Cerebrovascular and Chiari I malformations, although rare, have also been described in individuals with RAF-1 NS. To our knowledge, the presence of congenital occipital alopecia in an individual with NS has not been previously reported. We report a patient with a de novo pathogenic heterozygous RAF1 gene sequence variant, c.770C>T (p.Ser257Leu), with atypical scalp findings. Our proband was a 4-week-old female dichorionic, diamniotic twin born at 35 weeks 2 days gestation to nonconsanguineous parents. At birth, her length was 45.7 cm (14th centile), weight was 2656 g (69th centile), and head circumference was 34.5 cm (97th centile). The mother was 38 at the time of birth. There was no history of maternal or gestational diabetes. Prenatal ultrasound was concerning for cystic hygroma. The immediate neonatal course was complicated by acute respiratory failure, left ventricular outflow tract obstruction with concern for coarctation on echocardiogram, poor feeding, and failed newborn hearing screen which prompted transfer to a tertiary NICU for further management. At the time of consultation, the following problems had been identified: bilateral cataracts, significant redundant posterior neck folds that showed fatty soft tissue neck mass without a cystic component, and hypertrophic cardiomyopathy with elevated pulmonary arterial pressures. Physical exam was notable for relative macrocephaly with turricephaly, lowset, posteriorly rotated ears, redundant posterior neck folds, and a focal, 1cm circular area of alopecia at the midline occipital region. These findings were concerning for a RASopathy. Imaging of her superficial midline scalp defect with brain MRI showed a suspected atretic encephalocele, but CT did not reveal any occipital bony defects. After re-evaluation, it was confirmed that there was no intracranial connection or bony defect at the area of the congenital alopecia nor at the level of the suboccipital skin thickening/redundancy. Chromosomal microarray was nondiagnostic and thus exome sequence analysis was preformed which detected the pathogenic RAF1 variant. The diagnosis of RAF1 NS accounts for nearly all of the physical changes seen in our patient, particularly the severe degree of PHTN and HCM, with the exception of her occipital alopecia. Since our initial consultation, the patient continues to grow along NS-specific curve, has persistent mild bilateral hearing loss, and has had interval placement of gastric tube secondary to oral feeding difficulties. There has been mild improvement in cardiac function, septal hypertrophy, and PHTN. She remains seizure-free. This report expands the phenotype of RAF1 Noonan syndrome to include congenital focal alopecia. We recommend that NS should be added to the differential when this same scalp finding is present. Although the presence of this physical finding in our patient was not definitively associated with any underlying structural CNS or bony changes, this case highlights the importance of investigating with detailed cranial and spinal imaging to better characterize cerebral morphology and guide genetic testing in suspected RASopathy cases. Additional cases with this finding are needed to better understand potential associations.

Vitamin D Deficiency in Preschool Children with Down Syndrome

Vitamin D is a fat-soluble secosteroid prohormone that is produced on the skin by contact with sunlight. Through various metabolic changes in the body, it transforms into a hormone known as calcitriol, with a key role in the calcium and phosphate metabolism (1). Vitamin D serves plenty of functions in the body. Therefore, its deficiency may cause musculoskeletal symptoms such as bone pain, muscle weakness, gait difficulty, skeletal deformity, in addition to extraskeletal symptoms such as autoimmune diseases, cardiovascular diseases, and neuropsychiatric diseases (2). Down Syndrome occurs as a result of trisomy, which occurs due to an extra copy of the whole or part of the long arm of chromosome 21 and is the most commonly known cause of delay in development. DS affects 1 in every 787 liveborn babies (3). DS is often accompanied by distinctive craniofacial features, congenital heart disease and immune, musculoskeletal and endocrine system abnormalities (4,5). In patients with this syndrome, various environmental and hormonal factors such as hypotonia, low physical activity, poor calcium and vitamin D intake, intrauterine growth restriction, hypogonadism and thyroid dysfunction may contribute to bone mass and quality (6,7). Among all the others, vitamin D may have a crucial role in the health of these people. Vitamin D levels differ with many factors, including exposure to sunlight, dietary intake, and supplement use (8,9). There is a lack of scientific evidence on the prevalence and severity of vitamin D deficiency in children with DS. Hence, this study aimed to determine vitamin D deficiency in children with DS, from infancy to toddler and particularly during the preschool period, and to raise awareness on the matter.

Identification of de novo EP300 and PLAU variants in a patient with Rubinstein\u2013Taybi syndrome-related arterial vasculopathy and skeletal anomaly

Rubinstein–Taybi syndrome (RSTS) is a human genetic disorder characterized by distinctive craniofacial features, broad thumbs and halluces, and intellectual disability. Mutations in the CREB binding protein (CREBBP) and E1A binding protein p300 (EP300) are the known causes of RSTS disease. EP300 regulates transcription via chromatin remodeling and plays an important role in cell proliferation and differentiation. Plasminogen activator, urokinase (PLAU) encodes a serine protease that converts plasminogen to plasmin and is involved in several biological processes such as the proteolysis of extracellular matrix-remodeling proteins and the promotion of vascular permeability and angiogenesis. Recently, we discovered a patient who presented with RSTS-related skeletal anomaly and peripheral arterial vasculopathy. To investigate the genetic cause of the disease, we performed trio whole genome sequencing of the genomic DNA from the proband and the proband’s parents. We identified two de novo variants coined c.1760T>G (p.Leu587Arg) and c.664G>A (p.Ala222Thr) in EP300 and PLAU, respectively. Furthermore, functional loss of EP300a and PLAUb in zebrafish synergistically affected the intersegmental vessel formation and resulted in the vascular occlusion phenotype. Therefore, we hypothesize that the de novo EP300 variant may have caused RSTS, while both the identified EP300 and PLAU variants may have contributed to the patient’s vascular phenotype.

Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency

BackgroundThe spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter.Presentation of casesWe report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans.ConclusionsThis is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.

Natural history study of adults with Wolf-Hirschhorn syndrome 2: Patient-reported outcomes study.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene disorder consisting of prenatal and postnatal growth deficiency, distinctive craniofacial features, intellectual disability, and seizures. The condition is caused by a partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3). While there are many reports of individuals with WHS, useful data on long-term survival and life status of adults with the syndrome are very limited. There are only 11 reports of individuals over the age of 18 years in the literature. Establishing the medical manifestations of adults with WHS would be helpful in establishing appropriate health supervision guidelines. This study was one component of a two-part investigation on adults with WHS. This patient-reported outcomes study (PROS) was accomplished by using the registry of rare diseases at Sanford Research, Coordination of Rare Diseases (CoRDS)at Sanford. Thirty family members or caretakers of 30 adults with WHS/4p- entered into the CoRDS registry and completed some or all of the survey data. Twelve caretakers completed the recently-added survey on activities of daily living. Two of the individuals with WHS were partly independent while 10 required total care. The results provide novel information on daily life and independence in adults with WHS. Importantly, the majority of caretakers reported that the adults were in good health. The data from both parts of the study will contribute to our knowledge of the natural history of the syndrome and guide in establishing appropriate health supervision guidelines for adults with WHS.

Natural history study of adults with Wolf-Hirschhorn syndrome 1: Case series of personally observed 35 individuals.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene disorder, clinically delineated by prenatal and postnatal growth deficiency, distinctive craniofacial features, intellectual disability, and seizures. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3). Although more than 300 persons with WHS have been reported in the literature, there is sparse, if any, long-term follow-up of these individuals and thus little knowledge about course and potential further complications and health risks during adulthood and advanced age. This study attempted to assess medical conditions and function of adult individuals with WHS. It was one component of a two-part investigation on adults with WHS. The other part of the study is the patient-reported outcomes study reported elsewhere. About 35 individuals with WHS (26 females; nine males), aged between 19 and 55 years were recruited. About 25 individuals were personally observed at the IRCCS Stella Maris Foundation by A.B. and followed up between 5 and 20 years; and 10 were recruited from the 4p-Support Group, The United States. Of note, 23/35 (66%) are close to total care. About 11 out of 35 (31%) were partly self-independent, requiring supervision on certain daily routines, and 1 out of 35 (3%) was fully independent. However, a positive perspective is given by the overall good health enjoyed by the 66% of our cohort of individuals. Overall, quality of life and level of function into adulthood appear to be less critical than anticipated from previous studies.