Expanding the phenotype of neurofibromatosis type 1 microdeletion syndrome.

Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.

Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.

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.

Central nervous system involvement in individuals with RASopathies.

Central nervous system (CNS) anomalies are common in individuals with RASopathies. While certain findings, including relative or absolute macrocephaly, are typical for most RASopathies, other findings are more common in certain conditions, with rare low-grade gliomas in Noonan syndrome (NS); Chiari 1 malformation and tethered cord in Costello syndrome (CS); and variable structural anomalies including heterotopia and hydrocephalus in cardio-facio-cutaneous syndrome (CFC). We performed a literature review and present aggregate data on the common and uncommon CNS manifestations in individuals with RASopathies. A gene-based approach to defining risk for specific abnormalities may be considered. However, limited information on the CNS findings of rare RASopathies, such as autosomal recessive LZTR1-related NS or PPP1CB-related NS with loose anagen hair (NSLH), is currently available. Thus, consideration of the RASopathies as a group of distinct syndromic conditions with shared underlying causes and overlapping clinical presentations remains relevant, and individuals with a RASopathy are at risk for many findings seen in these conditions.

Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.

Primary ciliopathies are heterogenous disorders resulting from perturbations in primary cilia form and/or function. Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar/brain stem malformation, hypotonia, and developmental delays. At least 35 genes are associated with Joubert syndrome, including the gene KIAA0753, which is part of a complex required for primary ciliogenesis. The phenotypic spectrum associated with biallelic pathogenic variants in KIAA0753 is broad and not well-characterized. We describe four individuals with biallelic pathogenic KIAA0753 variants, including five novel variants. We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis. Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity. Correspondingly, KIAA0753 patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation. Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient-focused functional assays for proving causality of genetic variants.

Craniosynostosis is a feature of Costello syndrome.

Costello syndrome (CS) is an autosomal dominant disorder caused by pathogenic variants in HRAS. Craniosynostosis is a known feature of other RASopathies (Noonan and cardiofaciocutaneous syndromes) but not CS. We describe four individuals with CS and craniosynostosis and present a summary of all previously reported individuals with craniosynostosis and RASopathy.

Sleep Outcomes in Neonates with Pierre Robin Sequence Undergoing External Mandibular Distraction: A Longitudinal Analysis.

BACKGROUND: Robin sequence is a common cause of upper airway obstruction in newborns. Herein, we report sleep outcomes in neonates undergoing external mandibular distraction osteogenesis. METHODS: In this retrospective, 14-year, single-institution study of neonates with Robin sequence undergoing mandibular distraction osteogenesis, we compare respiratory parameters and sleep architecture before versus after surgery. RESULTS: Thirty-one neonates were included; age was 13 days (interquartile range, 5 to 34 days) at preoperative polysomnography and 80 days (interquartile range, 50 to 98 days) at postoperative polysomnography. All neonates had severe obstructive sleep apnea at baseline (defined as pre-operative obstructive apnea hypopnea index ≥ 10). Postoperatively, there was a significant reduction in obstructive apnea hypopnea index [38.3 (interquartile range, 23.4 to 61.8) preoperatively versus 9.4 (interquartile range, 5.3 to 17.1) postoperatively; p < 0.0001], and a significant improvement in sleep efficiency and oxygen saturation nadir. Although 26 neonates (84 percent) had a 50 percent reduction in obstructive apnea hypopnea index postoperatively, all neonates had obstructive sleep apnea, and 15 neonates (48 percent) had persistent severe obstructive sleep apnea following surgery. CONCLUSIONS: We report the largest cohort of sleep outcomes in neonates with Robin sequence and severe obstructive sleep apnea undergoing external mandibular distraction osteogenesis. Although the severity of obstructive sleep apnea improves postoperatively, the disease persists in all neonates. We propose that neonates undergo polysomnography before and soon after mandibular distraction osteogenesis to objectively assess improvement in obstructive sleep apnea, as they may require additional evaluation for sites of multilevel airway obstruction and treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Medically actionable comorbidities in adults with Costello syndrome.

Costello syndrome (CS) is an autosomal-dominant condition caused by activating missense mutations in HRAS. There is little literature describing health concerns specific to adults with CS. Parents of individuals with CS need to know what to anticipate as their children age. We surveyed a group of 20 adults and older adolescents with CS regarding their medical concerns and lifestyle characteristics. We identified several previously undescribed actionable medical concerns in adults with CS. First, the high prevalence of anxiety in this cohort indicates that screening for anxiety is warranted since this is a treatable condition that can have a significant impact on quality of life. Second, adults with CS should be monitored for progressive contractures or other problems that could decrease mobility. This is especially important in a population that seems to have increased risk for osteopenia. Finally, the lack of cancer diagnoses in adulthood is of interest, although the cohort is too small to draw definitive conclusions about cancer risk in adults with CS. Ongoing follow-up of the current cohort of adults with CS is necessary to delineate progressive medical and physical problems, which is essential for providing targeted management recommendations and anticipatory guidance to families.

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.

Fetal magnetic resonance imaging of skeletal dysplasias.

BACKGROUND: Fetal magnetic resonance imaging (MRI) is obtained for prenatal diagnosis and prognostication of skeletal dysplasias; however, related literature is limited. OBJECTIVE: The purpose of this study was to define the utility of fetal MRI for skeletal dysplasias and to report MRI findings associated with specific diagnoses. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board; informed consent was waived. Women referred for suspected fetal skeletal dysplasia who underwent MRI between January 2003 and December 2018 were included. Definitive diagnoses were determined by genetic testing, autopsy, physical examination and/or postnatal/postmortem imaging. Fetal MRI examinations and reports were reviewed. Descriptive statistics were used to summarize imaging findings. RESULTS: Eighty-nine women were referred for fetal MRI for possible skeletal dysplasia. Forty-three (48%) were determined to have a diagnosis other than skeletal dysplasia and nine were excluded for lack of specific skeletal dysplasia diagnosis. Thirty-seven cases of skeletal dysplasia with available fetal MRI and specific diagnosis were included for analysis. Diagnoses included achondrogenesis (n=2), achondroplasia (n=5), Boomerang dysplasia (n=1), campomelic dysplasia (n=2), Jeune syndrome (n=1), Kniest dysplasia (n=1), osteogenesis imperfecta (n=15) and thanatophoric dysplasia (n=10). A specific skeletal dysplasia diagnosis was mentioned in 17/37 (46%) of MRI imaging reports and correct for 14/17 (82%). MRI findings were reported for each specific skeletal dysplasia diagnosis. CONCLUSION: Fetal MRI is a useful diagnostic tool for skeletal dyplasias and excluded the diagnosis in nearly half of referred pregnancies. In addition to providing fetal lung volumes, fetal MRI demonstrates findings of the brain in achondroplasia and thanatophoric dysplasia, of the spine in achondroplasia and achondrogenesis, of the calvarium in osteogenesis imperfecta and thanatophoric dysplasia, and of the cartilage in Kniest dysplasia.

Costello syndrome: Clinical phenotype, genotype, and management guidelines.

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations. METHODS: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared. RESULTS: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years). CONCLUSIONS: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.

Longitudinal Sleep Outcomes in Neonates With Pierre Robin Sequence Treated Conservatively.

STUDY OBJECTIVES: Although Pierre Robin sequence (PRS) is a major cause of neonatal obstructive sleep apnea (OSA), longitudinal studies reporting evolution with age are lacking. This study aimed to describe changes in sleep-related respiratory parameters and sleep architecture in neonates with PRS treated conservatively (defined for this paper as treatment without tracheostomy or mandibular distraction). METHODS: A retrospective, 14-year, single-institution study of neonates with PRS who underwent diagnostic polysomnography (PSG) and at least one follow-up PSG. Those treated with surgery were excluded. Data were analyzed using a mixed-effects model with subject-specific random effect. RESULTS: In a cohort of 21 infants, baseline PSG (mean age 0.9 ± 0.7 months) showed a total apnea-hypopnea index (AHI) of 24.3 ± 3.6 events/h, obstructive apnea-hypopnea index (OAHI) of 13.4 ± 1.6 events/h, central apnea index of 10.2 ± 3.2 events/h, and an arousal index of 28.3 ± 1.3 events/h (variables reported as least square means ± standard error of the mean). There was a significant reduction in AHI, OAHI, arousal index, and percentage of REM sleep with advancing age. Although 71% of infants achieved full oral feeds by one month of age, some infants remained underweight during infancy. CONCLUSIONS: These neonates with PRS and OSA, treated conservatively, had an improvement in OAHI with advancing age with the median age of OSA resolution at 15 months. Factors potentially responsible include craniofacial growth and maturational changes of respiratory control. Further studies are necessary to determine the long-term effects of conservative management on growth and neurodevelopmental outcomes in these infants.

Management of Airway Obstruction in Infants With Pierre Robin Sequence.

BACKGROUND: Pierre Robin sequence (PRS)-related airway obstruction is often treated surgically; however, objective measures predicting the need for surgery are poorly defined. METHODS: A retrospective chart review was performed on 171 neonates with PRS. Infants were grouped based upon intervention modality: nonsurgical (conservative) or surgical [mandibular distraction osteogenesis (MDO) or tracheostomy]. Demographic data, physical examination findings, and study results were compared between groups to determine risk factors for surgical intervention, and to predict long-term success or failure of those interventions. RESULTS: The most significant, objective risk factor among those receiving surgery was a poor preintervention sleep study [obstructive index (OI): 42.4 versus 12.9 for the conservative treatment group; P < 0.001]. Only 11% of those treated conservatively had an OI >20, whereas 67.5% of those treated surgically met this severity measure. Of those receiving surgery, tracheostomy was associated with neurologic impairment (P = 0.030) and low birth weight (P = 0.046) compared with the MDO group. Together with syndromic status, these risk factors were useful for predicting failure of MDO to avoid subsequent tracheostomy (test sensitivity and specificity were 64.2% and 100.0%, respectively). No long-term differences in speech or micrognathia were detected between the 3 groups; however, those treated conservatively or with MDO had improved long-term feeding and airway obstruction outcomes compared with the tracheostomy group. CONCLUSIONS: Surgical intervention for PRS-related tongue-based airway obstruction should be strongly considered with an OI >20. Tracheostomy should be reserved for complex patients with concomitant syndromic diagnosis, neurologic impairment, and low birth weight.

Early-lethal Costello syndrome due to rare HRAS Tandem Base substitution (c.35_36GC>AA; p.G12E)-associated pulmonary vascular disease.

Costello syndrome is a rare, autosomal-dominant syndrome caused by activating missense mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS), most often p.G12S. Several rare mutations have consistently been associated with a more severe phenotype that is often lethal in infancy. Cause of death is most often respiratory failure, with hypertrophic cardiomyopathy playing a significant role in morbidity. Impaired fibroblast elastogenesis is thought to contribute to the Costello phenotype, but reports of histologic evidence of disordered elastogenesis at autopsy are limited. We report a patient with Costello syndrome due to a rare tandem base substitution (c.35_36GC>AA) resulting in the p.G12E missense change. The proband died at the age of 3 months from respiratory failure, with minimal evidence of cardiomyopathy. The autopsy disclosed pulmonary vascular dysplasia affecting small arteries and veins associated with abnormal elastin distribution in tortuous dilated arteries and veins, with nonuniform wall thickness and semiobstructive lesions at artery branch points typical of early pulmonary hypertensive vascular disease. Elastic fibers in the dermis were abnormally short and fragmented. This case suggests that disordered elastogenesis in the pulmonary vasculature and undiagnosed (or underdiagnosed) pulmonary hypertension may contribute to morbidity in patients with Costello syndrome.

Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia.

OBJECTIVE: Pulmonary hypoplasia is a major cause of death in lethal skeletal dysplasias. We hypothesize that in fetuses with prenatally diagnosed skeletal dysplasia, comparison of observed-to-expected (O/E) lung volume will help predict lethality. STUDY DESIGN: We conducted a retrospective chart review of patients referred for evaluation of suspected fetal skeletal anomalies. Twenty-three pregnancies were identified with confirmed fetal diagnosis of skeletal dysplasia for which fetal magnetic resonance imaging (MRI) was performed between 21 and 38 weeks of gestation and ultrasound biometry data were available. Femur length to abdominal circumference ratio (FL/AC) and O/E lung volumes were calculated. The association between O/E lung volume, FL/AC, and lethality was measured using logistic regression. RESULTS: Lethality was significantly associated with O/E lung volume (p = 0.002) and FL/AC (p = 0.0476). Analysis with receiver-operating characteristic curves suggested that O/E lung volume of 47.9% or FL/AC of 0.124 could be useful clinical cutoffs in the prediction of lethality. CONCLUSION: In fetuses with skeletal dysplasia, fetal MRI-derived O/E lung volume was predictive of lethality. When evaluating a fetal skeletal dysplasia, fetal MRI may be considered in cases for which ultrasound-based lethality prediction is ambiguous or uncertain in order to provide families with the most complete and accurate information.

A novel dominant COL11A1 mutation resulting in a severe skeletal dysplasia.

Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia, and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.

Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis.

Keutel syndrome is a rare, autosomal recessive disorder characterized by diffuse cartilage calcification, peripheral pulmonary artery stenosis, midface retrusion, and short distal phalanges. To date, 28 patients from 18 families have been reported, and five mutations in the matrix Gla protein gene (MGP) have been identified. The matrix Gla protein (MGP) is a vitamin K-dependent extracellular protein that functions as a calcification inhibitor through incompletely understood mechanisms. We present the clinical manifestations of three affected siblings from a consanguineous Turkish family, in whom we detected the sixth MGP mutation (c.79G>T, which predicts p.E27X) and a fourth unrelated patient in whom we detected the seventh MGP mutation, a partial deletion of exon 4. Both mutations predict complete loss of MGP function. One of the patients presented initially with a working diagnosis of relapsing polychondritis. Clinical features suggestive of Keutel syndrome were also observed in one additional unrelated patient who was later found to have a deletion of arylsulfatase E, consistent with a diagnosis of X-linked recessive chondrodysplasia punctata. Through a discussion of these cases, we highlight the clinical overlap of Keutel syndrome, X-linked chondrodysplasia punctata, and the inflammatory disease relapsing polychondritis.

Imperforate anus is a rare associated finding in blepharocheilodontic syndrome.

Blepharocheilodontic (BCD) syndrome is a rare autosomal-dominant condition that is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. It exhibits considerable phenotypic variability among affected individuals. An additional rare associated manifestation is imperforate a.u. (IA), which has been reported in three cases [Guyuron et al. (1995); J Craniofac Surg 6:392-394; Gorlin et al. (1996); Am J Med Genet 65:109-112; da Silva Lopes et al. (2003); Am J Med Genet Part A 121A:266-270]. Here we report on a family with BCD that includes IA, confirming that anorectal anomalies are a part of BCD syndrome.