Broad Nasal Bridge Research Articles

Developmental and epileptic encephalopathy 33 caused by EEF1A2 gene mutation: a case report

A boy, aged 7 months, presented with severe global developmental delay (GDD), refractory epilepsy, hypotonia, nystagmus, ocular hypertelorism, a broad nasal bridge, everted upper lip, a high palatal arch, and cryptorchidism. Genetic testing revealed a de novo heterozygous missense mutation of c.364G>A(p.E122K) in the EEF1A2 gene, and finally the boy was diagnosed with autosomal dominant developmental and epileptic encephalopathy 33 caused by the EEF1A2 gene mutation. This case report suggests that for children with unexplained infancy-onset severe to profound GDD/intellectual disability and refractory epilepsy, genetic testing for EEF1A2 gene mutations should be considered. This is particularly important for those exhibiting hypotonia, nonverbal communication, and craniofacial deformities, to facilitate a confirmed diagnosis.

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.

Three Familial Cases of Stickler Syndrome: A Case Report

Purpose: Stickler syndrome, a hereditary connective tissue disorder characterized by mutations in collagen genes, presents with progressive ophthalmopathy and diverse systemic manifestations. Here, we present three familial cases of Stickler syndrome, emphasizing the importance of early detection through clinical investigations and genetic testing.Case summary: Two generations of a family, a mother and her two daughters, were evaluated for Stickler syndrome. All three exhibited bilateral retinal lattice degeneration, perivascular retinal degeneration, and vitreous liquefaction. The daughters shared characteristic facial features, including a flattened face, broad nasal bridge, and micrognathia. Clinical symptoms and examination findings led to diagnoses of Stickler syndrome. Subsequent genetic testing in five family members confirmed a COL2A1 mutation in the three affected individuals.Conclusions: Stickler syndrome carries a high risk of vision loss from ocular complications, necessitating early detection and intervention. In addition, the presence of systemic manifestations, such as musculoskeletal joint disorders, mitral valve prolapse, hearing loss, and cleft palate, emphasizes the importance of prompt detection through appropriate clinical investigations and genetic testing.

Axenfeld-Rieger Syndrome (ARS): A Case Report

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant condition manifesting as a heterogeneous group of features. Of particular note are the ocular and craniofacial anomalies and dental features such as hypodontia, microdontia, taurodontism, enamel hypoplasia, conical-shaped teeth, shortened roots and delayed eruption. We report the case of a 23 years old female patient, who presented to the ophthalmology department for a routine eye chek-up. The ophthalmological examination showed vertical cup-to-disc ratio of 0,6 in the right eye and 0,7 in the left eye with normal intra ocular pressure. On general examination, she had maxillary hypoplasia, broad nasal bridge, oligodontia and microdontia.

De novo KAT6B mutation causes Say–Barber–Biesecker–Young–Simpson variant of Ohdo syndrome in an Iranian boy: a case report

BackgroundSay–Barber–Biesecker–Young–Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation.Case presentationA 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed.ConclusionWe present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

FRI325 Pituitary Stalk Interruption Syndrome Presenting As Short Stature: A Case Report

Abstract Disclosure: S. Ravindra: None. S. Tirupati: None. Background: Pituitary stalk interruption syndrome (PSIS) is a rare congenital pituitary anatomical defect that leads to a variable degree of pituitary hormone deficiency. The classic neuroimaging findings of this condition include thin or interrupted stalk, absent or ectopic posterior pituitary, and hypoplastic anterior pituitary gland. The reported incidence of PSIS is 0.5 per 1,00,000 live births. The exact pathophysiology of this syndrome is not fully understood, but chromosomal microdeletions and perinatal asphyxia have some established roles in the literature as primary miscreants. Here we report a case of an adolescent male child who presented with complaints of short stature and absent secondary sexual characters development, diagnosed with PSIS following an MRI. Clinical Case: A 16-year-old male child was referred to the endocrinology department for the evaluation of short stature and delayed secondary sexual character development. This patient was born out of a non-consanguinous marriage and delivered at term by the vaginal route, with no other significant perinatal or family history. Psychomotor milestones were attained appropriately as per age but had poor linear growth. On examination, he had short stature - height 146cms (-2.7 SDS), weight: 53.5kg BMI: 23.5 Kg/m2 with normal vitals. Head-to-toe examination revealed immature facies, deep-seated eyes, broad nasal bridge, bilateral lipomastia, high-pitched voice, Tanner stage: A1P1, SPL:4cms, the testicular volume of 3cc bilaterally, with rest of the system-wise examinations being normal. Routine laboratory investigations (CBC, RFT, LFT, Electrolytes) were within normal limits. Bone age: 13years. The hormonal assessment showed central hypothyroidism, hypocortisolemia, and GH insufficiency, with pre-pubertal gonadotropin levels- suggestive of pan-hypopituitarism (Table 1). MRI pituitary showed anterior pituitary hypoplasia with interrupted stalk, and ectopic posterior pituitary, with no other brain anomalies which is consistent with the diagnosis of PSIS. The patient was initiated on hormone replacement therapy, currently taking hydrocortisone, growth hormone, levothyroxine, and testosterone. Conclusion: PSIS is a rare condition, that can present with various spectrum of clinical features. Signs and symptoms may not be evident in the neonatal and infancy period, therefore diagnosis is often delayed. Early diagnosis and treatment are crucial for preventing adverse effects of long-term hormonal deficiencies and improving the quality of life. Presentation: Friday, June 16, 2023

Lamb-Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency.

Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.

Expanding the genotypic and phenotypic spectrum of the SPTBN4 gene mutation: A new variant and dysmorphology

Congenital hypotonia and neuropathy caused by SPTBN4 mutation are the core findings of a newly defined rare syndrome: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness. Although hearing loss secondary to auditory neuropathy, dysmorphic findings, and epilepsy are distinctive features, they are not present in every patient, leading to a wide range of phenotypic spectrum. We report here a male patient with the SPTBN4 gene mutation presenting with core symptoms but not hearing loss and epilepsy. There were also previously unreported dysmorphic findings such as prominent eyebrows, bilateral constant esotropia, microphthalmia, bitemporal narrowing, low hairline, low-set ears, broad nasal bridge, bulbous nose, anteverted nares, and high-arched palate, broadening the phenotypic spectrum even further. In conclusion, both genetic background and phenotypic features of the SPTBN4 mutations were expanded in our report. After exclusion of spinal muscular atrophy in patients with congenital hypotonia and areflexia, the SPTBN4 mutations should be considered.

0997 Severe mixed sleep apnea in a patient with epilepsy and gene mutation EEFIA2

Abstract Introduction EEFIA2 gene mutation has been linked with epilepsy and intellectual disability. There have been case series and case reports in the past that have linked the gene mutation with both epilepsy and possible phenotypes of broad nasal bridge and tented upper lip. In previous cases, there has been no description of work up of sleep disordered breathing. Here, we present a case of sleep apnea in a patient with intractable epilepsy and gene mutation. Report of case(s) Patient is a toddler-aged female with epilepsy. She was diagnosed with infantile epileptic encephalopathy with a pathogenic mutation in EEF1A2 gene with intractable generalized myoclonic epilepsy, hypotonia, and developmental delay. She has been on several seizure medications in an effort to obtain seizure control. With medications she has been undergoing side effects of swallowing difficulties and increased sedation. During her neurology epilepsy follow up, she was noted to have frequent nighttime awakenings. She was scheduled to have a combined polysomnography and 24-hour electroencephalogram. Polysomnography performed which showed evidence of severe mixed central and obstructive sleep apnea-hypopnea syndrome with AHI of 100/h, CAI 42/H, OAHI - 57/h, and REM AHI of 106/h. Video Electroencephalogram performed at the same time and showed multiple atonic and myoclonic seizures with multifocal discharges. Patient was evaluated by otolaryngology and was not a candidate for surgical interventions. She was titrated on bilevel positive airway pressure during a split titration sleep study. Conclusion Genetic mutations and their phenotypes are becoming more widely addressed and researched. In this case we present a rare genetic mutation EEFIA2 which has presented as intellectual disability, hypotonia, and intractable epilepsy in this patient. Given some daytime somnolence and nighttime awakenings, a polysomnography was pursued and showed severe obstructive sleep apnea. In cases where phenotypes are not widely known, it is important to screen for sleep disorders. Support (if any)

First Arch Syndrome: A Case Report on Crouzon Syndrome

Wide spectrum of anomalies in the first branchial arch gives rise to a variety of congenital syndromes mainly affecting the lower jaw, ear or mouth during early embryonic development. Crouzon syndrome, one of many craniosynostosis syndrome, is an autosomal dominant disorder caused by mutation in Fibroblast Growth Factor Receptor (FGFR)-2 and -3 gene. Here, we report a case of 7 years old male patient who presented to us with features of brachycephaly, exophthalmos, flat broad nasal bridge and low set ears. Keywords: First arch syndrome, Craniofacial dysostosis, exophthalmos, copper beaten appearance

Ranbp1 modulates morphogenesis of the craniofacial midline in mouse models of 22q11.2 deletion syndrome.

Facial dysmorphology is a hallmark of 22q11.2 deletion syndrome (22q11DS). Nearly all affected individuals have facial features characteristic of the syndrome: a vertically long face with broad nasal bridge, narrow palpebral fissures and mild micrognathia, sometimes accompanied by facial skeletal and oropharyngeal anomalies. Despite the frequency of craniofacial dysmorphology due to 22q11.2 deletion, there is still incomplete understanding of the contribution of individual 22q11 genes to craniofacial and oropharyngeal development. We asked whether homozygous or heterozygous loss of function of single 22q11 genes compromises craniofacial and/or oropharyngeal morphogenesis related to these 22q11DS phenotypes. We found that Ranbp1, a 22q11DS gene that mediates nucleocytoplasmic protein trafficking, is a dosage-dependent modulator of craniofacial development. Ranbp1-/- embryos have variably penetrant facial phenotypes, including altered facial morphology and cleft palate. This 22q11DS-related dysmorphology is particularly evident in the midline of the facial skeleton, as evidenced by a robustly quantifiable dysmorphology of the vomer, an unpaired facial midline bone. 22q11DS-related oropharyngeal phenotypes reflect Ranbp1 function in both the cranial neural crest and cranial ectoderm based upon tissue-selective Ranbp1 deletion. Analyses of genetic interaction show that Ranbp1 mutation disrupts BMP signaling-dependent midline gene expression and BMP-mediated craniofacial and cranial skeletal morphogenesis. Finally, midline defects that parallel those in Ranbp1 mutant mice are observed at similar frequencies in the LgDel 22q112DS mouse model. Apparently, Ranbp1 is a modulator of craniofacial development, and in the context of broader 22q11 deletion, Ranbp1 mutant phenotypes mirror key aspects of 22q11DS midline facial anomalies.

Morphometric analysis of the size-adjusted linear dimensions of the skull landmarks revealed craniofacial dysmorphology in Mid1-cKO mice

BackgroundThe early craniofacial development is a highly coordinated process involving neural crest cell migration, proliferation, epithelial apoptosis, and epithelial-mesenchymal transition (EMT). Both genetic defects and environmental factors can affect these processes and result in orofacial clefts. Mutations in MID1 gene cause X-linked Opitz Syndrome (OS), which is a congenital malformation characterized by craniofacial defects including cleft lip/palate (CLP). Previous studies demonstrated impaired neurological structure and function in Mid1 knockout mice, while no CLP was observed. However, given the highly variable severities of the facial manifestations observed in OS patients within the same family carrying identical genetic defects, subtle craniofacial malformations in Mid1 knockout mice could be overlooked in these studies. Therefore, we propose that a detailed morphometric analysis should be necessary to reveal mild craniofacial dysmorphologies that reflect the similar developmental defects seen in OS patients.ResultsIn this research, morphometric study of the P0 male Mid1-cKO mice were performed using Procrustes superimposition as well as EMDA analysis of the size-adjusted three-dimensional coordinates of 105 skull landmarks, which were collected on the bone surface reconstructed using microcomputed tomographic images. Our results revealed the craniofacial deformation such as the increased dimension of the frontal and nasal bone in Mid1-cKO mice, in line with the most prominent facial features such as hypertelorism, prominent forehead, broad and/or high nasal bridge seen in OS patients.Conclusion While been extensively used in evolutionary biology and anthropology in the last decades, geometric morphometric analysis was much less used in developmental biology. Given the high interspecies variances in facial anatomy, the work presented in this research suggested the advantages of morphometric analysis in characterizing animal models of craniofacial developmental defects to reveal phenotypic variations and the underlining pathogenesis.

Novel variant of TMEM231 in Meckel syndrome: a case report

A 34-year-old woman underwent routine antenatal ultrasound scanning at 17 weeks gestation which identified multiple fetal abnormalities including severe oligohydramnios, growth restriction, occipital encephalocele, short and bowed long bones, bilateral enlarged multicystic kidneys and an absent bladder. As the findings were highly suspicious for a lethal fetal ciliopathy, the patient received counselling and elected for a medical termination of pregnancy at 19 weeks. Autopsy confirmed the imaging findings, additionally demonstrating low set ears, micrognathia, a broad nasal bridge, polysyndactyly and bilateral hypoplastic lungs.

Hyper-IgE syndrome with recurrent infections — An autosomal dominant multisystem disorder

Hyper IgE syndrome (HIES) is a rare disorder characterized by eczema, recurrent infections of the skin and lungs, typically with Staphylococcus aureus, Candida albicans and certain viruses, and elevated levels of serum IgE. Other clinical manifestations include characteristic facies (prominent forehead, broad nasal bridge and facial asymmetry), chronic eczematous dermatitis, retained primary dentition, recurrent pathological fractures, hyper-extensibility and scoliosis. The respiratory system involvement in HIES has been reported with HRAD. Here we presented a case of HIES with rare associations of Hyperreactive airway disease.

PSUN339 Persistent Hypoglycemia and Hyperinsulinism in a Patient With Kabuki Syndrome Type 1.

Abstract Background Transient neonatal hypoglycemia typically resolves within the first few days of life. Persistence of neonatal hypoglycemia is a more significant finding that warrants further investigation. Clinical case A 2-year-old female born at 37 weeks of gestation via C-section due to a history of maternal preeclampsia. Delivery was complicated by meconium aspiration syndrome for which the patient was admitted to the NICU where she had a prolonged course. Patient was initially depressed at birth with APGARs of 3/6/8 at 1, 5 and 10 minutes of life, respectively. During the neonatal period, she had multiple complications including GERD, FTT (G-tube was placed), recurrent UTIs, congenital heart disease (mild RVH and ASD) and hypoglycemia. Regarding her hypoglycemia, the initial work up was suggestive of hyperinsulinism with a critical sample remarkable for a BG: 57 mg/dl (60-100mg/dl), Insulin level: 8.3 uUm/mL Subsequent glucagon challenge test confirmed hyperinsulinism. She initially required a continuous glucose infusion and Diazoxide was started. She was discharged home on Diazoxide and Diuril. Subsequently, Diazoxide was successfully discontinued at the age of 2 months. A Congenital Hyperinsulinism genetic panel was negative for the most frequent mutations. At 11 months old, she presented to our clinic due to persistent hypoglycemia when enteral feeds were attempted to be spaced. Patient was started on cornstarch which was discontinued secondary to frequent diarrhea. SolCarb was started with enteral feeds with good tolerance and response, maintaining target blood glucose levels. On physical examination, she had some dysmorphic features that were suggestive of a syndromic condition: prominent ear lobes, broad and flat nasal bridge, a single prominent tooth at the center of the bottom gum line, long palpebral fissures with upward curvature at the lateral edges, prominent finger pads and neurodevelopmental delay. Since she had features suggestive of Kabuki syndrome, WES was ordered which was remarkable for a pathogenic mutation in KMT2D (Autosomal dominant, Heterozygous, variant c.5269C>T and p.R1757X). Conclusion Persistent hypoglycemia beyond the neonatal period is a rare finding in Kabuki syndrome. In addition, it is a more common finding in Kabuki Syndrome type 2 (Mutations in the KDM6A gene). Our patient presents a rare case of a 2-year-old female with persistent hypoglycemia and hyperinsulinism secondary to KS1. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Intellectual developmental disorder with dysmorphic facies and ptosis caused by copy number variation including the BRPF1 gene in Peruvian patient

BackgroundIntellectual developmental disorder with dysmorphic facies and ptosis (MIM #617333) is a very rare condition, characterized by more than 80% by language delay, intellectual disability, gross motor development delay, broad nasal bridge, hypertelorism, and hypotonia. This condition exhibits as autosomal dominant inheritance and is caused by a heterozygous variant in the BRPF1 gene. Additionally, the copy number variation in the terminal region of chromosome 3p (MIM #613792) has been shown to manifest in most patients as intellectual disability, motor delay, and hypotonia.Case presentationWe present an 18-year-old male patient with facial dysmorphism, intellectual disability, ptosis, and congenital heart disease. Using chromosomal microarray analysis, a previously unreported 90 kb deletion involving seven genes was found.ConclusionWhen comparing our findings with 39 previous reports, we found that the common clinical features of this syndrome, such as gross motor delay, hypotonia, and congenital spinal cord abnormalities, were not observed in this patient. From the seven genes implicated in the deletion, only BRPF1 could be strongly correlated with the phenotype, according to its function and haploinsufficiency coefficients.

A rare case of lethal Raine syndrome presenting with facial dysmorphism and pyriform aperture stenosis

Raine syndrome is a very rare autosomal recessive disorder characterized by osteosclerosis, periosteal bone formation and distinct facial abnormalities that include microcephaly and low set ears osteosclerosis, cleft palate, gum hyperplasia, broad and depressed nasal bridge and proptosis. Patients affected with this syndrome have a mutation in FAM20C gene located on 7p22.3. This gene is responsible for phosphorylation of Serine residues on an enzyme casein kinase which helps in mineralisation of the bones.

Identification of MMACHC and ZEB2 mutations causing coexistent cobalamin C disease and Mowat-Wilson syndrome in a 2-year-old girl

Cobalamin C (cblC) disease and Mowat-Wilson syndrome (MWS) are rare hereditary diseases. To date, there have been no reports of people suffering from these two genetic diseases, or whether there is any correlation between the two diseases. We reported a 2-year-old girl with both cblC disease and MWS. The patient initially manifested as slow weight gain, hypotonia, broad nasal bridge, high forehead, high palate arch, ear crease, patent ductus arteriosus, atrial and ventricular septal defect and bilateral mild ventriculomegaly in the neonatal period. However, as the baby grew older, the typical facial features became more prominent, and overall developmental delays were noted at the subsequent follow-up, with the motor and cognitive development significantly lagging behind that of other children of the same age. At 26 days old, laboratory tests revealed remarkably elevated levels of serum homocysteine, C3/C2 and urine organic acid. Whole-exome sequencing detected compound heterozygous variants in MMACHC, including one previously reported mutation [c.609G > A (p.W203X) and a novel missense mutation[ c.643 T > C (p.Y215H)]. The computer simulations of the protein structure analysis of the novel missense mutation showed the variant p.Y215H replaced a neutral amino acid with a strongly basic lysine, which broken the local structure by changing the carbon chain skeleton and decreasing the interaction with adjacent amino acid. This is expected to damage the utilization of vitamin B12 and influence the synthesis of AdoCbl and MeCbl, contributing to its pathogenicity. Thus, clinical and genetic examinations confirmed the cblC disease. Another heterozygous variant in ZEB2 [NM_014795; loss1(exon:2–10)(all); 127901 bp] was detected by whole-exome sequencing. The heterozygous 3.04 Mb deletion in EB2 [GRCH37]del(2)(q22.2q22.3) (chr2:142237964–145274917) was also confirmed by genome-wide copy number variations (CNVs) scan, which was pathogenic and led to the diagnosis of Mowat-Wilson syndrome. The biochemical indicators associated with cblC disease in the patient were well controlled after treatment with vitamin B12 and betaine. Here, a patient with coexisting cblC disease and MWS caused by different pathogenic genes was reported, which enriched the clinical research on these two rare genetic diseases.

Genetic Interaction of Thm2 and Thm1 Shapes Postnatal Craniofacial Bone.

Ciliopathies are genetic syndromes that link skeletal dysplasias to the dysfunction of primary cilia. Primary cilia are sensory organelles synthesized by intraflagellar transport (IFT)—A and B complexes, which traffic protein cargo along a microtubular core. We have reported that the deletion of the IFT-A gene, Thm2, together with a null allele of its paralog, Thm1, causes a small skeleton with a small mandible or micrognathia in juvenile mice. Using micro-computed tomography, here we quantify the craniofacial defects of Thm2−/−; Thm1aln/+ triple allele mutant mice. At postnatal day 14, triple allele mutant mice exhibited micrognathia, midface hypoplasia, and a decreased facial angle due to shortened upper jaw length, premaxilla, and nasal bones, reflecting altered development of facial anterior-posterior elements. Mutant mice also showed increased palatal width, while other aspects of the facial transverse, as well as vertical dimensions, remained intact. As such, other ciliopathy-related craniofacial defects, such as cleft lip and/or palate, hypo-/hypertelorism, broad nasal bridge, craniosynostosis, and facial asymmetry, were not observed. Calvarial-derived osteoblasts of triple allele mutant mice showed reduced bone formation in vitro that was ameliorated by Hedgehog agonist, SAG. Together, these data indicate that Thm2 and Thm1 genetically interact to regulate bone formation and sculpting of the postnatal face. The triple allele mutant mice present a novel model to study craniofacial bone development.

СИНДРОМ ЯКОБСЕНА: ОБЗОР ЛИТЕРАТУРЫ И ОПИСАНИЕ КЛИНИЧЕСКОГО НАБЛЮДЕНИЯ

Jacobsen syndrome (JS) is a rare chromosomal anomaly caused by a deletion of the distal part of the long arm of chromosome 11, characterized by a variable phenotype, including delayed physical development, mental retardation, autism, facial skeletal dysmorphia (skull deformity, hypertelorism, ptosis, coloboma, anti-mongoloid eye incision, epicanthus, broad nasal bridge, short nose, v-shaped mouth, small ears, low-set ears that are rotated backward), multiple visceral malformations (heart, kidney, gastrointestinal tract, genitals), and of CNS and skeletal system, thrombocytopenia/thrombocytopathy or pancytopenia and combined immunodeficiency. The article presents a clinical case of a patient with JS with characteristic facial anomalies, neurological manifestations and immunological disorders, including humoral and cellular immunodeficiency.