Closure Of Anterior Fontanelle Research Articles

FGF Signaling Regulates Development of the Anterior Fontanelle.

The calvarial bones of the infant skull are connected by transient fibrous joints known as sutures and fontanelles, which are essential for reshaping during birth and postnatal growth. Genetic disorders such as Apert, Pfeiffer, Crouzon, and Bent bone dysplasia linked to FGFR2 variants often exhibit multi-suture craniosynostosis and a persistently open anterior fontanelle (AF). This study leverages mouse genetics and single-cell transcriptomics to determine how Fgfr2 regulates closure of the AF closure and its transformation into the frontal suture during postnatal development. We find that cells of the AF, marked by the tendon/ligament factor SCX, are spatially restricted to ecto- or endocranial domains and undergo regionally selective differentiation into ligament, bone, and cartilage. Differentiation of SCX+ AF cells is dependent on FGFR2 signaling in cells of the osteogenic fronts which, when fueled by FGF18 from the ectocranial mesenchyme, express the secreted WNT inhibitor WIF1 to regulate WNT signaling in neighboring AF cells. Upon loss of Fgfr2 , Wif1 expression is lost, and cells of the AF retain a connective tissue-like fate failing to form the posterior frontal suture. This study provides new insights into regional differences in suture development by identifying an FGF-WNT signaling circuit within the AF that links frontal bone advancement with suture joint formation.

Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).

Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.

Tuticaj telesne težine na razvoj sekundarnih centara osifikacije i termina zatvaranja velike fontanele kod odojčadi

Introduction: during the infant development, the organ growth is influenced by genetic factors, diet, hormones and many neuropeptides. The secondary ossification center in the hip joint begins to form around the 4th month of life. Primary dentition begins at the age of 5-6 months with the emergence of the central incisor in the maxilla. At birth, 6 fontanelles are present between the plate bones of the cranium. The largest is the anterior or large fontanelle. Objective of our research is to analyze the development of the secondary ossification center in the femoral head in relation to dentition and closure of the anterior fontanelle closure as well as influence of childrens' birth weight and current weight on these processes. Methodology: The study included 284 infants, male and female, aged 3 to 8 months. Clinical examination of the musculoskeletal system, anthropomentric measurements and ultrasonographic findings of the hip joint were performed at the Pediatric Clinic of the Clinical Hospital Center Pristina in Gracanica. Results: The development of secondary ossification centre correlated with child's age, dentition, anterior fontanelle closure, birth weight and delivery method, as well as actual body weight. Anterior fontanelle size was inversely related to age, body weight and secondary ossification. Conclusions: According to regression analysis, body weight is the only factor that has a direct and independent impact on the onset and progression of ossification process. Every additional kilogram of a child's body weight accelerates secondary ossification by 1.3-3.77 times.

Anterior fontanelle closure and diagnosis of non-syndromic craniosynostosis: a comparative study using computed tomography

ObjectiveSuspicion of early anterior fontanel (AF) closure is a common reason for referral to a pediatric neurosurgeon because of the suspected increased risk of developing craniosynostosis (CS) in spite of the absence of evidence in the literature. The aim of this study was to analyze the association between AF closure and the diagnosis of non-syndromic CS in Brazilian children. MethodsAn observational and case-cohort study was conducted to compare the incidence of closed AF between healthy children (group 1) and children diagnosed with non-syndromic CS (group 2) at a pediatric neurosurgery referral center. The accuracies of completely closed AF and diagnosis of CS were assessed. ResultsHigh-resolution three-dimensional reconstruction computed tomography scans were obtained for 140 children aged < 13 months, of whom 62.9% were boys and 37.1% were girls (p < 0.001). The most common types of non-syndromic CS were trigonocephaly (34, 48%) and scaphocephaly (25, 35.7%). Closed fontanel (27, 38.6%) was observed in both groups, and a sensitivity of 36.1%, specificity of 72%, the positive predictive value of 59%, and negative predictive value of 51% were observed in the patients diagnosed with CS when AF closure occurred before the age of 6 months. ConclusionThe results of this comparative study of AF closure and CS diagnosis suggest that early AF closure does not imply a diagnosis of CS. Pediatricians should be aware of the risk of misdiagnosis of CS in cases with a widely open AF in spite of the presence of CS.

Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Spontaneous external rupture of hydrocephalus after fontanelle closure: a case report and review of literature

We report a 2-year-old child with congenital hydrocephalus who presented with a frontal meningocoele due to ventriculo-subgaleal fistula secondary to hydrocephalus (internal rupture), which gradually ruptured spontaneously through the skin. This case is unique given its association with occipital encephalocele and is only the second case to present with external rupture beyond the age of 1 year. Further, the ventricles have ruptured through the skull, after the closure of anterior fontanelle, into the subgaleal space. It challenges the present understanding that external rupture occurs only through an open anterior fontanelle.

Neurodevelopmental risk evaluation of premature closure of the anterior fontanelle.

To evaluate neurological development of completely healthy children with anterior fontanelle premature closure via Denver Developmental Screening Test II and to compare the results with control group. The records of 140 patients applied to Mersin University Pediatric Neurology Outpatient Clinic between 2011 and 2019 with the complaint of premature closure of the anterior fontanelle were retrospectively reviewed. Patients with microcephaly, craniosynostosis, infection, sequelae of hypoxia-ischemia, metabolic disorders, intracranial hemorrhage, epilepsy, endocrine problems, and dysmorphic features were excluded from the study. Sixty-six completely healthy children with anterior fontanelle premature closure were included in the study. Denver Developmental Screening Test II was performed by the same developmental specialist to the children with premature closure of the anterior fontanelle as well as to the healthy control group. For each child included in the case and the control group, 90% of the values for each development area were calculated and recorded. Then, the results were compared. Denver II Developmental Screening Test (p < 0.001) and gross motor subtest (p < 0.001) results showed statistically significant retardation in the case group compared with the control group. The study was the first study in the literature on the gross motor development of children with premature closure of anterior fontanelle, and it has been found significantly undeveloped compared with the control group, and it has been concluded that similar patients should be evaluated from this view point in pediatric neurology department.

Risk factors for delayed speech in children aged 1-2 years

Background Speech delay is one of the most common developmental delays in children. To minimize the negative outcomes of speech delay, risk factors should be explored to help in early patient diagnosis.&#x0D; Objectives To assess for associations between delayed speech in children aged 1 to 2 years and possible risk factors including gender, gestational age, birth weight, asphyxia during birth, head circumference, anterior fontanelle closure, gross motor development, duration of breastfeeding, caregiver identity, number of siblings, exposure to gadgets and television, and social interaction.&#x0D; Methods Parents of children aged 1 to 2 years who were treated at Dr. Cipto Mangunkusumo Hospital, and Klinik Anakku, Pondok Pinang in Jakarta from January 2018 to March 2018 were interviewed. Data were processed with SPSS Statistics for Mac and analyzed by Chi-square test and logistic regression method.&#x0D; Results Of 126 subjects, 63 children had speech delay and 63 children had normal speech development. Multivariate analysis revealed that the significant risk factors for delayed speech were delayed gross motor development (OR 9.607; 95%CI 3.403 to 27.122; P&lt;0.001), exclusive breastfeeding for less than 6 months (OR 3.278; 95%CI 1.244 to 8.637; P=0.016), and exposure to gadgets and television for more than 2 hours daily (OR 8.286; 95%CI 2.555 to 26.871; P&lt;0.001).&#x0D; Conclusion Delayed gross motor development, exclusive breastfeeding for less than 6 months, media exposure for more than 2 hours daily, and poor social interaction are risk factors for delayed speech development in children.

Distal Arthrogryposis with Impaired Proprioception and Touch: Description of an Early Phenotype in a Boy with Compound Heterozygosity of PIEZO2 Mutations and Review of the Literature

The recessive PIEZO2-associated disease, distal arthrogryposis with impaired proprioception and touch (DAIPT), is characterized by hypotonia, perinatal respiratory distress, significantly delayed motor milestones, and progressive symptoms of distal arthrogryposis and scoliosis. Here, we describe the youngest patient with DAIPT to date, who, at the age of 3.5 years, did not show a single clinical sign of distal arthrogryposis or contractures, but had a history of bilateral clubfoot operations. On the contrary, he presented with some features, not described thus far, such as syringohydromyelia, a small cyst of the spinal cord, moderate microcephaly with premature closure of anterior fontanelle, and spontaneous unilateral patella dislocation at the age of 32 months. Using whole exome sequencing, we identified 2 new different loss-of-function mutations in the PIEZO2 gene in our patient. We also review the phenotypes of all 16 previously published patients with DAIPT, summarize the distinctive clinical features of this rare genetic disorder, and recommend that DAIPT be included in the differential diagnosis of floppy infant. PIEZO2 is a unique ion channel that converts mechanical impulses into cellular signals and is involved in various mechanotransduction pathways. In addition to DAIPT, mutations in PIEZO2 have been described to cause 3 more distinct phenotypes of distal arthrogryposis, which are dominant and associated with gain-of-function mutations. On the contrary, recessive DAIPT is associated with loss-of-function PIEZO2 mutations.

Closure of the anterior and posterior fontanelle in the New Zealand population: A computed tomography study.

Significant ethnic variation has been demonstrated in the closure of the anterior fontanelle (AF); however, to date, this has not been investigated in the Māori/Pasifika population. The computed tomography scans of 163 individuals (116 Māori/Pasifika and 47 New Zealand (NZ) European) aged between birth and 4 years were retrospectively analysed to investigate the surface area (SA) and time of closure of the anterior and posterior fontanelles in New Zealand. The Māori/Pasifika group showed clinical AF closure (SA < 114 mm2 ) rates of 25% at 4-6 months, increasing to 47% at 10-12 months and 80% at 13-18 months. The posterior fontanelle was clinically unfused in 17% of the Māori/Pasifika group aged <1 month and in 7% of the 1-3-month-old group. No cases of posterior fontanelle non-fusion were identified in the NZ European population. This study establishes normal values for AF size and closure frequency for the first time in the paediatric Māori/Pasifika population.

Prevalence of sub-clinical vitamin-D deficiency and hypothyroidism in children aged 18- 36 months with open anterior fontanelle: a cross-sectional study

Background: The range of normal closure time of the anterior fontanelle (AF) is generally regarded to be 4 to 26 months. The objectives of this study was to find out the prevalence of subclinical vitamin D deficiency and hypothyroidism in children aged 18-36 months with open AF.Methods: This is a hospital based, cross-sectional study done over a period of 24 months, in which thyroid function tests and 25-hydroxy-vitamin D levels were done for healthy children aged 18-36 months with open AF; the latter was also done for equal numbers (n=30) of age and sex matched children with closed AF for control values. The mean vitamin D levels and proportion of children of various categories based on vitamin D levels among both the groups were compared.Results: Open AF was seen in 37 children. Seven of them had obvious causes of delayed AF closure and were excluded. In the remaining 30 children, none of the children had abnormal thyroid function tests. 23.3% of the study group had low vitamin D levels; but, the levels were low even in 37% of control group. The mean vitamin D level of the study group (39.05±17.11 ng/ml) was similar to the control group (37.3±14.74 ng/ml).Conclusions: Neither subclinical vitamin D deficiency nor subclinical hypothyroidism accounted for delayed AF closure in this study.

What is the age distribution for anterior fontanelle closure in healthy infants?

EVIDENCE-BASED ANSWER The median age of anterior fontanelle closure is 14 to 16 months, with 90% to 96% closing by 24 months of life (SOR: C, cross-sectional studies, cohort, and retrospective studies).

Cleidocranial dysplasia: A rare case report

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal disorder, characterized by delayed closure of anterior fontanelle, absent or hypoplastic clavicles, dental problems, and short stature. Usually, the presenting complaints are open anterior fontanelle and dental abnormalities. We hereby present a 5-year-old Indian child who presented to us with the complaints of persistently open anterior fontanelle and short stature. A detailed, thorough examination and high degree of suspicion in a child presenting with persistent open fontanelle has a great importance in the diagnosis of a genetic syndrome like CCD.

Quantification of the timing of anterior fontanelle closure in a Western Australian population

Closure of the anterior fontanelle is generally accepted to occur within the first two years of life. However, statistical quantification of the precise timing of closure in a Western Australian population has not been explored. The current study examined MDCT scans of 68 individuals between birth and 3.91 years to assess the timing of anterior fontanelle closure. Using OsiriX, the scans are viewed in axial and multi-planar reconstructed (MPR) images and three-dimensional volume rendered reconstructions. Anterior fontanelle fusion status was quantified using two methods: calculating anterior fontanelle area and by taking the oblique linear distances of the open fontanelle. The single greatest proportion of fusion was shown to occur in the first year of life, by which stage only 47.19% of the fontanelle remains unfused (on average by area). There was only one individual demonstrating complete fusion before 1 year of age (0.86 years) with no single individual presenting an open fontanelle beyond 2.4 years of age. The current study outlines statistically quantitated data that facilitates forensic age estimation (either macroscopic or radiographic) specific to Australian individuals from the perinate to early childhood life stages.

Autosomal dominant Kenny-Caffey syndrome with congenital hypoparathyroidism, short stature and normal intellect: a case report

Kenny-Caffey syndrome (KCS) is characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form (KCS Type 2) caused by mutations in FAM111A is distinguished from the autosomal recessive form (KCS Type1), caused by mutations in TBCE gene, by the absence of mental retardation. Our proband presented on day 8 of life with hypocalcaemic seizures secondary to hypoparathyroidism. Normocalcaemia was achieved with IV calcium gluconate and maintained by oral calcium carbonate 100mg BD and calcitriol 0.1mcg BD for the first 2 years of life while serum PTH remained low at <0.3pmol/L. There has been no evidence of nephrocalcinosis on follow up. The dose of supplemental calcium and calcitriol is being gradually reduced. She also has persistent mild microcytic anaemia with normal iron stores. Her phenotype included small hands and feet, triangular hypoplastic and dystrophic nails, hypoplastic mid-face, macrocrania and large persistent fontanelles. Karotype and FISH for 22q11 deletion were normal. Initial investigations included a normal ECHO, renal ultrasound and MRI brain. Her neurodevelopment is normal but her growth is compromised. At 1 year, her length was 65.5cms (SDS -2.9) and at 3 years, her height was 80cms (SDS -3.8). There is no family history of short stature or hypoparathyroidism. She is growth hormone sufficient on pharmacological testing; however she has been commenced on growth hormone treatment based on her poor growth velocity and short stature. It is currently too early to determine response. A skeletal survey performed at 2 years of age was suggestive of KCS. Genetic testing revealed a heterozygous mutation c.1622C>A (p.Ser541Tyr) in FAM111A. However, the unusual nails, the reducing calcium requirement and the unexplained microcytic anaemia are unique to our patient. Written informed Consent for this patient has been taken including results of the genetic analyses and images according to the Institutional Ethics Committee procedures of our health service.

Incidentally detected intracranial sewing needle in a child—A case report

Abstract A 4-year-old boy with normal physical and mental development presented to the emergency room with minor head injury and skin laceration on the right frontal region following an accidental fall in a ditch while playing with other kids. At presentation, he had normal neurologic examination. The skull X-ray showed a 4.5 cm long sewing needle-like foreign body, which was later confirmed by cranial computed tomography scanning. There was no suspected entry at the corresponding location to suggest an acute penetrating injury. This object may have penetrated during early infanthood before closure of anterior fontanelle. A nonsurgical management was opted because there were no neurological complaints, even after a three-year follow-up.

Anterior fontanelle closure and size in full-term children based on head computed tomography.

This study investigates radiographically acquired normative ranges of anterior fontanelle closure (AFC) and surface area (SA) in healthy full-term infants. High-resolution head computed tomography (CT) scans were retrospectively reviewed for AFC and AF dimensions to allow approximation of AF SA. Between 15 and 23 head CT scans per monthly age-group (0-24 months) were reviewed, totaling 464 scans. AFC frequency increased steadily from age 10 (16%) to 20 months (88%), reaching higher than 50% at age 16 months (53%). The AF was closed in 3% to 5% of infants at 5 to 6 months. AF median SA increased from 769.3 mm(2) (age 0 months) to 1022.2 mm(2) (2 months), then declined steadily. This study provides reference charts detailing AFC frequency and AF SA as a function of age. Wide variability of AFC timing and AF size among healthy infants suggest that early or delayed AFC may represent normal variants.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

The Transcriptional corepressorTle4 Is a Novel Regulator Of Murine Hematopoietic Stem and Progenitor Cells and Their Niche

We previously identified Transducin-like/Enhancer of Split 4 (TLE4) as a potential tumor suppressor gene in acute myeloid leukemia whose loss appears to complement AML1-ETO induced leukemia. In this study we examined the role of Tle4 in normal hematopoiesis. Using Tle4 knockout mice we demonstrated that Tle4 is critical for maintaining a supportive hematopoietic stem cell niche, and also has intrinsic effects on HSC survival and B-cell differentiation.Tle4 knockout mice exhibit profound defects in bone mineralizationTle4 knockout mice become runted by 2 weeks of age and generally die by the time of weaning. These mice exhibit a profound defect in mineralization of the bone and bone marrow failure by 3.5 weeks. At birth KO mice showed a significant reduction in the degree of calcification of the skull and long bones, despite no significant differences in overall body size or weight at this early time point. This was confirmed by Von Kossa staining for calcified bone of one-day old tibiae from KO and WT mice. At 21-28 days after birth trabecular bone was almost absent in tibiae and femurs with thin cortices of the long bones. These data indicate Tle4is critical for proper bone mineralization. In further support of this novel role of Tle4 in skeletal development, a mutation in TLE4 has recently been identified in a father and daughter with congenital vertebral malformations including delayed anterior fontanelle closure, shortened vertebral pedicles and kyphoscoliosis.Tle4 deficient bone marrow stroma is defective in supporting hematopoietic stem and progenitor cellsTo determine if the hematopoietic abnormalities in Tle4 KO mice might in part be due to the observed defects in the skeletal or stromal compartment of the BM, we cultured WT LKS cells on WT or KO stromal cells obtained at 2 weeks, prior to the observation of bone marrow hypoplasia. In WT cocultures, 6-15% of recovered cells were positive for both c-kit and Sca-1. In stark contrast, less than 1% of cells were C-kit+Sca-1+, when WT LKS cells were plated in KO stromal cocultures. Long-term coculture experiments in methylcellulose revealed an even more pronounced effect, with cells recovered from WT cocultures generating on average 10-fold more colonies than cells recovered from KO cocultures. Some KO cocultures failed to exhibit any colony forming ability. Therefore, these data suggest that Tle4-/- stromal cells cannot maintain and support HSPC growth as efficiently as WT stromal cells. In addition, Western blots of whole bone lysates from two week old mice showed that the majority of Tle4 KO mice had a reduction in Scf protein levels.Tle4 deficient hematopoietic stem cells exhibit cell intrinsic defects in B-cell differentiation and survivalDue to the progressive leukopenia in primary Tle4 KO mice, and the extrinsic effects noted above, we sought to determine whether loss of Tle4 intrinsically affected self-renewal and repopulation efficiency of HSC in serial transplantation assays using BM and fetal liver cells.Whole BM from two-week-old KO and WT animals transplanted into lethally irradiated allogeneic CD45.1 mice showed similar levels in donor chimerism in blood, but significant reductions in the frequency of B cells in KO transplanted mice at 16 weeks. At 32 weeks after transplant, recipient mice of KO BM developed significant leucopenia, mostly due to a decreased frequency of B cells. To exclude any effects of the bone marrow stroma we also performed serial transplantations from fetal livers of embryonic day 13.5 WT and KO fetuses. In this transplant model, both peripheral leukopenia and specific B cell lymphopenia were observed in primary transplant recipients, recapitulating the phenotype observed in recipients of KO BM. Although in the primary transplants no difference in the frequency of HSC between recipients of KO or WT BM was observed, progressively with secondary and tertiary transplants we observed a striking hematopoietic stem cell exhaustion with reduction in LKS cells, CD34-LKS cells, and LKS CD34-CD48-CD150+ long term HSC.Taken together, these data indicates Tle4 is a critical regulator of hematopoiesis acting by maintaining supportive function of the bone marrow niche as well as intrinsically affecting B-cell differentiation and the survival of hematopoietic stem cells. Disclosures:No relevant conflicts of interest to declare.

A recurrent de novo FAM111A mutation causes kenny–caffey syndrome type 2

Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation.