Search

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.

International audience; Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.

Cole-Carpenter syndrome is a rare skeletal dysplasia associated with low-bone mass or an osteogenesis imperfecta (OI)-like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15-year-old Japanese boy with short stature of the short-trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole-Carpenter syndrome. He had low-bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2.

OBJECTIVES: In tests on known individuals macroscopic sex estimation has between 70% and 98% accuracy. However, materials used to create and test these methods are overwhelming modern. As sexual dimorphism is dependent on multiple factors, it is unclear whether macroscopic methods have similar success on earlier materials, which differ in lifestyle and nutrition. This research aims to assess the accuracy of commonly used traits by comparing macroscopic sex estimates to genetic sex in medieval English material. MATERIALS AND METHODS: Sixty-six individuals from the 13th to 16th century Hospital of St John the Evangelist, Cambridge, were assessed. Genetic sex was determined using a shotgun approach. Eighteen skeletal traits were examined, and macroscopic sex estimates were derived from the os coxae, skull, and os coxae and skull combined. Each trait was tested for accuracy to explore sex estimates errors. RESULTS: The combined estimate (97.7%) outperformed the os coxae only estimate (95.7%), which outperformed the skull only estimate (90.4%). Accuracy rates for individual traits varied: Phenice traits were most accurate, whereas supraorbital margins, frontal bossing, and gonial flaring were least accurate. The preauricular sulcus and arc compose showed a bias in accuracy between sexes. DISCUSSION: Macroscopic sex estimates are accurate when applied to medieval material from Cambridge. However, low trait accuracy rates may relate to differences in dimorphism between the method derivative sample and the St John's collection. Given the sex bias, the preauricular sulcus, frontal bossing, and arc compose should be reconsidered as appropriate traits for sex estimation for this group. ispartof: AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY vol:168 issue:2 pages:340-351 ispartof: location:United States status: published

5q11.2 Deletion is a very rare genomic disorder, and its clinical phenotype has not yet been characterized. This report describes a patient with an 8.6 Mb deletion, showing hypotonia, mild developmental delay, short stature, and distinctive dysmorphic features (frontal bossing, square face, deep-set eyes, prominent columella, long philtrum, thin lips). © 2016 Wiley Periodicals, Inc.

Saul-Wilson syndrome (SWS) is a rare congenital skeletal syndrome characterized by postnatal onset of short stature, relative microcephaly, frontal bossing, prominent eyes with shallow orbits, midface hypoplasia, cataract, and generalized skeletal changes, including spondylar dysplasia, overtubulation of the long bones with metaphyseal flaring and megaepiphyses, coxa valga, elbow deformity, and brachydactyly. We describe a boy with the overall clinical and radiological features fitting the characteristics of SWS, although cataract, elbow deformity, and overt brachydactyly were not seen. He presented with painful hip joint due to hip subluxation in late childhood, which exacerbated with age and ultimately, required surgical intervention. Awareness of this orthopedic complication in SWS is essential in the management of patients with SWS. © 2015 Wiley Periodicals, Inc.

Achondroplasia and Down syndrome are relatively common conditions individually. But co-occurrence of both conditions in the same patient is rare and there have been no reports of fetal analysis of this condition by prenatal sonographic and three-dimensional (3-D) helical computed tomography (CT). Prenatal sonographic findings seen in persons with Down syndrome, such as a thickened nuchal fold, cardiac defects, and echogenic bowel were not found in the patient. A prenatal 3-D helical CT revealed a large head with frontal bossing, metaphyseal flaring of the long bones, and small iliac wings, which suggested achondroplasia. In a case with combination of achondroplasia and Down syndrome, it may be difficult to diagnose the co-occurrence prenatally without typical markers of Down syndrome.

Craniosynostosis is defined as a premature fusion of at least one cranial suture, which can be accompanied by other findings. Of syndromic cases, 14–22% have been associated with chromosomal rearrangements. This report describes a Brazilian boy with syndromic craniosynostosis who also presented with intellectual disability, microcephaly, frontal bossing, bitemporal narrowing, short neck, syndactyly, and cardiac defects. Chromosome banding showed an apparently normal male karyotype. Subsequent chromosomal microarray analysis (CMA) using the Affymetrix CytoScan 750 K Array showed a duplication of 2.1 Mb on chromosome 17q and a deletion of 1.4 Mb on chromosome 20q. The data suggested an unbalanced translocation, which was confirmed by fluorescence in-situ hybridization analysis (FISH). While there are several reports in the literature of chromosome 17q duplication syndrome accompanied by partial monosomies of other chromosomes, this is the first case featuring partial monosomy of 20q. The patients phenotype is generally consistent with 17q duplication syndrome, however craniosynostosis has rarely been associated with this chromosomal anomaly. © 2014 Wiley Periodicals, Inc.

Objectives To test the fetal profile (FP) line, defined as the line that passes through the anterior border of the mandible and the nasion, as a reference line for forehead and mandible anomalies. Methods Volumes of 248 normal and 24 pathological fetuses (1636 and 1937?weeks gestation, respectively) were analysed retrospectively. When the FP line passes anteriorly, across or posteriorly to the frontal bone, this was defined as negative, zero or positive, respectively. When the FP line was positive the distance (F distance) between the FP line and the frontal bone was measured. Results No cases with a negative FP line were found in the normal fetuses. Before 27?weeks gestation the FP line was always zero except in one case. After 27?weeks gestation the FP line was positive in up to 25% (F distance (mean, range): 2.8, 2.13.6?mm). The FP line correctly identified 13 cases with retrognathia, 5 cases with frontal bossing and 3 cases with a sloping forehead. Conclusion Although large prospective studies are needed, the FP line may be a useful tool to detect second trimester profile anomalies such as retrognathia, sloping forehead and frontal bossing with the possibility of quantifying the latter. (c) 2012 John Wiley & Sons, Ltd.

Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. We report on a patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. Our patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient.

We describe a 2-year-old boy born to healthy, consanguineous parents. He had craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, and low-set ears. In addition, he had curly, light hair, and oval hypomelanotic patches in the abdomen, lower limbs and back and one hyperpigmented patch in the groin without acanthosis nigricans. Cranial three-dimensional CT scan showed right-coronal, sagittal, and lambdoid suture synostoses. His cranial MRI at 2-months of age showed left hemimegalencephaly, hypoplasia of corpus callosum, and an abnormal configuration of hippocampus. In spite of these cranial findings, he had mild developmental delay and his neurological examination showed symmetric strength, tone and reflexes. Apart from febrile seizures, there was no history of epilepsy. The proband developed asymmetric hydrocephalus at the age of 18 months that required third ventriculostomy. Post-operative cranial MRI showed Chiari I- like malformation and asymmetry of cerebral hemispheres but less dysplastic cerebral cortex. Mutation analysis of FGFR3 showed a c.749C > G, p.Pro250Arg substitution. To the best of our knowledge, these manifestations have not been reported in patients with Muenke syndrome.

Background: The term cutis tricolor describes the combination of congenital hyper- and hypopigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported: (i) as a purely cutaneous trait; (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (iii) as a distinct type [cutis tricolor parvimaculata]; (iv) in association with other (e.g. vascular) skin disturbances. Objectives: To delineate the spectrum of skeletal defects in cutis tricolor. Methods: Retrospective and prospective analysis of skeletal surveys in 14 subjects (eight men; six women; aged 2–28 years) with cutis tricolor [4 purely cutaneous trait; 10 syndromic (RHS)]. Results: Bone abnormalities were recorded in 71.4% (10/14) of patients [100% (10/10) of cases with (other-than-skeletal) extra-cutaneous manifestations vs. null (0/4) in cases with purely cutaneous traits] and included overall small skull (n = 6); prognathism (n = 6); ‘J’-shaped pituitary fossa (n = 1); absence of atlas posterior arch (n = 3); frontal bossing (n = 6); scoliosis (n = 9) with kyphosis (n = 6) and/or lordosis (n = 6); vertebral (n = 9) and ribs (n = 4) defects. Negative ZFHX1B gene analyses excluded overlaps with Mowat–Wilson syndrome. Conclusions: Cutis tricolor may be a marker of underlying skeletal involvement particularly in subjects with a complex syndromic (RHS) phenotype.

The major diagnostic manifestations in Sotos syndrome include frontal bossing, downward slanting palpebral fissures, a prominent jaw, learning disability, and childhood overgrowth. Over 90% of clinically diagnosed patients have an abnormality in the NSD1 gene. We investigated the dental manifestations of this disorder and found one or several premolar teeth were absent in 9 out of 13 (69%) affected children and adolescents. A heterozygous mutation in the NSD1 gene was identified in 12 patients, including all patients with hypodontia. The severity of the hypodontia seemed to increase with the severity of aberration of the NSD1. More than 50% of the patients had enamel defects or excessive tooth wear. Dental age, based on tooth formation, was within the normal range. A characteristic occlusion for Sotos syndrome could not be identified. As agenesis of premolars was a common feature in these patients affected with Sotos syndrome, we recommend panoramic radiography at the age of 7 years. If premolars are missing, proper preventive and restorative care is necessary to maintain the deciduous molars. © 2009 Wiley-Liss, Inc.

Multisutural craniosynostosis that includes bilateral lambdoid and sagittal synostosis (BLSS) results in a very characteristic head shape with frontal bossing, turribrachycephaly, biparietal narrowing, occipital concavity, and inferior displacement of the ears. This entity has been reported both in the genetics literature as craniofacial dyssynostosis and in the surgical literature as "Mercedes Benz" syndrome. Craniofacial dyssynostosis was first described in 1976 by Dr. Neuhauser when he presented a series of seven patients with synostosis of the sagittal and lambdoid sutures, short stature, and developmental delay. Over the past 30 years nine additional patients with craniofacial dyssynostosis have been reported in the literature adding to the growing evidence for a distinct craniosynostosis syndrome. The term "Mercedes Benz" syndrome was coined by Moore et al. in 1998 due to the characteristic appearance of the fused sutures on three-dimensional CT imaging. In contrast to the aforementioned reported cases of craniofacial dyssynostosis, all three patients had normal development. Recently, there have been several case reports of patients with BLSS and distinct chromosomal anomalies. These findings suggest that BLSS is a heterogeneous disorder perhaps with syndromic, chromosomal, and isolated forms. In this manuscript we will present the largest series of patients with BLSS and review clinical, CT, and molecular findings.

Summary. Osteopathia striata is an unusual skeletal condition that can affect the bones of the skull quite markedly and result in dental problems that have rarely been discussed in the literature. The characteristic features exhibited by the patient in this case report were dense maxillary and mandibular bone, a high forehead with frontal bossing, a broad nasal bridge, prominent zygomatic arches and thickened angles of the mandible. The mouth opening was limited as a result of sclerosis of the mastoid process, and right lateral excursion of the mandible was reduced, probably because of a deformity of the left condyle. Resume. l'osteopahie striee est une affection rare du squelette qui peut aussi toucher les os du crâne de facon importante. Les problemes dentaires ont raremont ete rapportes dans la litterature. Dans le cas etudie, les traits caracteristiques etaient des os mandibulaires et maxillaires denses, un front haut avec bosse frontale, un nez large, des arcades zygomatiques proeminentes et un epaissisement des angles mandibulaires. l'ouverture buccale etait limitee en raison de la sclerose de la region mastoidienne et les mouvemets lateraux de la mandibule etaient reduits en raison, probablement, de la deformation du condyle gauche. Zusammenfassung. Striare Osteopathic ist eine ungewohnliche Erkrankung des Skeletts, die sich stark auf das Knochengewebe des Schadels auswirken und zu Zahnerkrankungen fuhren kann. Die charakteristischen Anzeichen, die der Patient in diesem Fallbericht aufwies, waren kompakte Ober-und Unterkiefer, eine hohe Stirn mit Wolbungen, ein breiter Nasenrucke, vorstehende Jochbogen und verdickte Kieferwinkel. Der Mund konnte aufgrund einer Sklerose des Warzenfortsatzes nur beschrankt geoffnet werden. Ferner war die rechte seitliche Bewegung des Unterkiefers eingeschrankt—wahrscheinlich aufgrund eine Deformitat des linken Kondylus. Resumen. La osteopathia striata es una condicion esqueletica poco usual que afecta a los huesos del craneo muy marcadamente y resulta en problemas dentales que han sido raramente discutidos en la literatura. Las caractensticas mostradas por el paciente en este reporte de caso fueron un hueso maxilar y mandibular muy denso, frente amplia con proyectura, puente nasal ancho, arcos zigomaticos prominentes y angulos mandibulares ensanchados. La aperture bucal estuvo muy limitada como resultado de la esclerosis del proceso mastoideo; los movimientos laterales de la mandibula estuvieron reducidos, probablemente debido a la deformidad del condilo izquierdo.

Deletions of chromosome bands 2p11.2 and 2p12 are rare, and only six patients have been reported to date. Here, we report on a 5-year-old girl with an 11.4 Mb interstitial deletion of chromosome bands 2p11.2-p12 and the characterization of this deletion by high-resolution array CGH. The patient presented with mental retardation, microcephaly and short stature. Facial features included broad nasal bridge, frontal bossing and mild dolichocephaly. Phenotypic comparison with previously published patients failed to reveal a consistent clinical pattern apart from developmental delay/mental retardation, which is probably due to different sizes and/or positions of the individual deletions. Among the 40 known genes deleted in our patient is REEP1, haploinsufficiency of which causes autosomal dominant spastic paraplegia type 31 (SPG31, OMIM 610250). Additional patients with well-characterized deletions within 2p11.2 and 2p12 will be needed to determine the role of individual genes for the clinical manifestations.

We report on a consanguineous Lebanese family where two sibs had an axial hypotonia, developmental delay, hirsutism, large fontanels with delayed closure, and dysmorphic facial features that consist of frontal bossing, prominent eyes, slightly down-slanting palpebral fissures, hypertelorism, telecanthus, long eyelashes, gum hypertrophy, and pointed chin. In addition, they had short neck, abnormal thoracic configuration, wrinkled skin on the hands and abdomen, hepato-splenomegaly and neonatal spontaneous fractures. Their overall health and hepatic function deteriorated every time they had fever. The eldest boy died at the age of 18 months secondary to a hepatic failure. Laboratory exams did not reveal any anomaly except for the hepatic function. Differential diagnoses are discussed and the possibility that we might be reporting on a new metabolic syndrome is raised.

We describe the clinical features of Robinow syndrome in the children of four Turkish couples. All the patients had cardinal features of this condition, such as short stature, frontal bossing, hypertelorism, short upturned nose with anteverted nares, micrognathia, mesomelic shortening of the forearms, vertebral and costal anomalies and hypoplastic genitalia. In contrast to reports in the literature, one patient showed extensive webbing of the toes and epigastric hernia. Parental consanguinity was present in two of the four cases. To our knowledge, at least 80 cases have been reported in the literature to date, including 19 cases born to Turkish couples in addition to our four cases. The evidence suggests that the frequency of Robinow syndrome is relatively higher in Turkey than in other areas of the world.

A Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the long bones and sclerosis of the craniofacial bones. Affected patients show macrocephaly, ocular hypertelorism, frontal bossing, broad nasal bridge and abnormalities of the palate. Anomalies such as hearing loss, congenital heart defect, vertebral anomalies and mental impairment have also been reported. Pedigree analysis has suggested an autosomal dominant inheritance, but a recent report of a family with significantly more affected males than females suggested the possibility of X-linked inheritance. Here we describe a new family with OS-CS (the twelfth in the literature) with four affected individuals (two males and two females) spanning three generations. The affected male in the third generation was stillborn with multiple congenital anomalies, whereas the other three affected individuals had mild features. This family may represent another example of X-linked OS-CS where the mutated gene(s) is more severe in males.

We report a patient with Antley-Bixler syndrome and review 13 patients from the literature. The cardinal features of this condition include craniosynostosis, severe mid-face hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long-bone fractures and femoral bowing, urogenital abnormalities and a normal karyotype. Early death was identified in 54% of the reported cases, usually due to respiratory complications. The oldest patient at the time of follow up was 10 years of age. Intellectual performance has been variable (developmental testing of our patient at 30 months of age showed a range of developmental skills equivalent to 6 to 11 months of age). Chronic respiratory distress, especially if accompanied by periods of apnea, may be important in the causation of mental retardation. Some patients with the syndrome have normal intelligence, which suggests a normally developing brain, particularly if a craniectomy is performed to treat sutural synostosis and indicates that there may be secondary factors (e.g., apnea) playing a role in the mental retardation (as seen in our patient with a history of apnea) in patients with the Antley-Bixler syndrome. Since choanal atresia/stenosis which diminishes the airway passage is a cardinal feature of this syndrome, choanal stenting should be performed on those patients with this finding during infancy to decrease the airway obstruction. All patients followed beyond infancy were ambulatory, including our patient at 35 months of age, who will take steps with assistance. Although most cases are sporadic, there were reports of recurrence in siblings of both sexes in two families, suggesting an autosomal recessive mode of inheritance.

Hb Dhofar is a variant haemoglobin (beta(29 (GGC-GGT) gly-gly), beta(58 (CCT-CGT) pro-arg)) associated with a thalassaemic phenotype and unique to the Sultanate of Oman. We report clinical and haematological data on 54 subjects with Hb Dhofar (37 heterozygotes, 14 homozygotes and three compound heterozygotes with a different beta-thalassaemia mutation). In heterozygotes, the level of Hb Dhofar ranged from 8.8% to 21.5%. All heterozygotes had Hb A2 > 3.5%, consistent with beta-thalassaemia trait. Hb Dhofar in homozygotes and compound heterozygotes ranged from 26% to 59.7%, with a peripheral film consistent with homozygous beta-thalassaemia. Age at presentation in homozygotes ranged between 6 months and 8 yr, with a majority presenting before 5 yr of age. All had splenomegaly and six (43%) had undergone splenectomy. All had some degree of frontal bossing and in particular, two patients with infrequent transfusions had marked thalassaemic facies and stunting of growth. Hb Dhofar can be mistaken for Hb D as the electrophoretic mobility is similar, but differs from it by a variable and reduced quantity of variant Hb in both heterozygotes and homozygotes. Clinical and haematological data suggest that this mutation behaves like a moderately severe beta(+) thalassaemia allele resulting in a thalassaemia intermedia phenotype.

Background: Rates of rickets from 15.9 to 26.7% have been reported in China. Methods: Combining the methods of epidemiology and the behavioral sciences, this study investigated the prevalence of rickets in children in rural Shanxi Province, China. A total of 250 children age 12–24 months were examined physically for the presence of rickets, blood was drawn for laboratory analysis, and X-rays were taken of each child’s wrists. Results: Vitamin D deficiency in the spring was found among 65.3% of children. Rickets diagnosis relying on clinical signs alone determined a rickets prevalence of 41.6%, declining to 17.0% in the fall after a summer of sun exposure (χ2 = 8.356, P = 0.004). But an integrated diagnostic method exploiting clinical signs, X-ray and alkaline phosphatase levels found the prevalence of active rickets to be 3.7%. Furthermore, it was demonstrated that only five clinical signs reflect active rickets – wide wrists, frontal bossing, rachitic rosary, Harrison’s sulcus, and bowed legs. Conclusions: The prevalence of active rickets in young children in northern China is lower than previously reported. Even in poor countries, simple tests such as X-rays and alkaline phosphatase can be added to physical examination to more accurately diagnose active rickets.

Objectives To examine the possible association of skull deformity and the development of the cranial sutures in fetuses with Apert syndrome. Methods Three-dimensional (3D) ultrasound was used to examine the metopic and coronal sutures in seven fetuses with Apert syndrome at 22–27 weeks of gestation. The gap between the frontal bones in the transverse plane of the head at the level of the cavum septi pellucidi was measured and compared to findings in 120 anatomically normal fetuses undergoing routine ultrasound examination at 16–32 weeks. Results In the normal group, the gap between the frontal bones in the metopic suture at the level of the cavum septi pellucidi, decreased significantly with gestation from a mean of 2.2 mm (5th and 95th centiles: 1.5 mm and 2.9 mm) at 16 weeks to 0.9 mm (5th and 95th centiles: 0.3 mm and 1.6 mm) at 32 weeks. In the seven cases with Apert syndrome, two-dimensional ultrasound examination demonstrated the characteristic features of frontal bossing, depressed nasal bridge and bilateral syndactyly. On 3D examination there was complete closure of the coronal suture and a wide gap in the metopic suture (15–23 mm). Conclusion In normal fetuses, cranial bones are believed to grow in response to the centrifugal pressure from the expanding brain and proximity of the dura to the suture is critical in maintaining its patency. In Apert syndrome, the frontal bossing may be a mere consequence of a genetically predetermined premature closure of the coronal suture. Alternatively, there is a genetically predetermined deformation of the brain, which in turn, through differential stretch of the dura in the temporal and frontal regions, causes premature closure of the coronal suture and impaired closure of the metopic suture. Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd.

Two sisters from a Lebanese family presented with slight developmental delay, short stature, congenital microcephaly, frontal bossing, mild hyperplastic supra-orbital ridges, broad nasal root, small dysplastic low-set ears, high arched palate, short neck, and hearing impairment. In addition, the oldest affected sister had esophageal atresia and the other sister had cleft palate. Temporal bone abnormalities included hypoplasia of the external auditory canal, small middle ear cavity, abnormal ossicles, and inner ear malformations with enlarged vestibular acqueducts. Differential diagnosis is discussed, and the possibility of a newly recognized autosomal recessive syndrome is raised.

We describe two unrelated patients who each have a similar chromosome 2 with duplication of 2p23 to pter, and deletion of 2q37 to qter. In one, the abnormality was derived from his mother with a pericentric inversion. Both individuals have frontal bossing; abnormally formed, low set and posteriorly rotated ears; redundant nuchal skin; inversion of the nipple(s); fleshy fingertips with prominent pads; a sacral dimple; significant developmental delay/mental retardation; and G-tube dependency. Most of these features are present in previously described individuals with either duplication of the 2p terminus or deletion of the 2q terminus. This report is the first that documents postnatal viability of individuals with concurrent duplication of 2p and deletion of 2q, and also generation of this imbalance through rearrangement of a maternally inherited pericentrically inverted 2. This report should be considered in the reproductive counseling of individuals with pericentric inversions of chromosome 2.

A new case of macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) syndrome is described. The patient presented typical congenital findings in utero, although the syndrome was diagnosed postnatally. The M-CMTC syndrome should be considered when there is a marked fetal overgrowth and progressive macrocephaly with no indications of maternal hyperglycemia or fetal hyperinsulinism. Our patient also had unilateral pleural effusion, curved femur and frontal bossing.

Phylloid hypermelanosis is a less clearly defined pigmentary disturbance than its hypopigmented counterpart, phylloid hypomelanosis. We report the case of a 32-month-old boy who had multiple melanotic macules arranged in a typical phylloid pattern since birth. He also had an abnormal facial appearance, with macrocephaly, frontal bossing, hypertelorism, internal strabismus, and auricular deformities. Psychomotor delay, multiple cystic brain lesions, and bilateral sensorineural hearing loss were also found. A review of associated anomalies as described in this and five previously reported patients with phylloid hypermelanosis shows some vague and inconsistent similarities, such as unusual facial appearance, malformed ears, hearing loss, and mental deficiency, but it is likely that phylloid hypermelanosis represents a class of heterogeneous phenotypes. Future clinical and genetic research may show how many distinct entities can be placed in this group of disorders.

Dolichospondylic dysplasia (DD) is a rare skeletal dysplasia primarily characterized by tall vertebral bodies and disproportionate short stature. Radiographic manifestations include tall vertebral bodies and gracile bones of the hands. Patients usually have eye and ear findings in addition to borderline mental retardation; however, tall vertebral bodies and slender tubular bones are also seen in the 3-M syndrome. Patients with the 3-M syndrome have a characteristic face with a triangular shape, frontal bossing, a flattened malar region, full eyebrows, a short nose with a bulbous tip, upturned nares, and full lips. We present two unrelated patients who share a distinct phenotype and have tall vertebral bodies, overtubulation of long bones, and short tubular bones of the hands and feet. We discuss the overlapping and distinguishing features between DD and the 3-M syndrome. Patient 1 was a 13-year-old female, and patient 2 was an unrelated adult female. These patients had normocephaly and short stature. They shared a common phenotype consisting of mild malar hypoplasia, a narrowed nasal body with a fleshy tip, full lips, and normal intelligence. In addition, they showed mild hand and foot abnormalities. These two patients lack many of the typical clinical features of both DD and the 3-M syndrome. They share a common phenotype and likely represent a distinct disorder. The spectrum of disorders with tall vertebral bodies as a key feature may include different entities that may be further defined with the characterization of the molecular defect(s).

We report on a Thai family with dominantly inherited malformation syndrome with upper limb anomalies, short stature, quadricuspid aortic valve, and minor craniofacial anomalies. The affected individuals comprised a mildly affected mother, a moderately affected daughter, and a most severely affected son. The daughter and son had short stature. The craniofacial abnormalities comprised frontal bossing, hypoplastic nasal bones, depressed nasal bridge, and broad nasal alae. The upper limb defects varies among the patients, ranging from radial ray defects in the mother through radial and ulnar ray defects with unilateral humeral hypoplasia in the daughter to radial ray defects with severe oligodactyly and bilateral humeral hypoplasia in the son. All patients in this family had hypoplasia of the shoulder girdle and resembled what is observed in many families with Holt-Oram syndrome. Moreover, the son showed quadricuspid aortic valve with mild aortic regurgitation. However, the present family did not show any mutation of the TBX5 gene, a disease-causing gene of Holt-Oram syndrome. The present family deserves further investigation on other genes that play a role in the development of the upper limbs, particularly of radial rays.

Schinzel-Giedion syndrome comprises multiple congenital anomalies. The orofacial features include coarse facies, frontal bossing, ocular hypertelorism, anterior open bite and macrodontia. Two cases are presented in which the presence of specific craniofacial anomalies with bilateral hydronephrosis confirmed the diagnosis. In one patient, bottle-feeding was associated with caries in maxillary central and lateral incisors, but the second patient was permanently tube fed and did not experience any dental caries. Clinical management of these patients requires a coordinated approach from a team of medical and dental specialists.

Monozygotic twin brothers are described who share clinical features which include: moderate mental retardation, short stature, macrocephaly, frontal bossing, ptosis, low-set ears, brachydactyly, 5th fingers clinodactyly, single palmar creases, cryptorchidism, and prelingual sensorineural deafness. One of the twins presented with mild cardiac dilatation and died at age 3½ from cardiac arrest during an episode of acute respiratory infection. While chromosome analyses performed for both twins on peripheral blood showed apparently normal karyotypes, screening for all telomeric regions on the surviving propositus revealed a combination of partial 6p trisomy and partial 11q monosomy. A balanced reciprocal translocation was found in the father. The phenotype of the twins is most likely related to this cryptic chromosomal rearrangement. The fact that the phenotype in this family partially overlaps with some previously reported phenotypes is discussed. © 2002 Wiley-Liss, Inc.

We present a rare case of a paediatric myelodysplastic syndrome (MDS) with congenital anomalies (frontal bossing and premature closure of anterior fontanelle). The case showed the clinical and biological features of a refractory anaemia excess blasts (RAEB). Bone marrow (BM) cytogenetics demonstrated a hyperdiploid karyotype, with several numerical abnormalities and unidentified rearrangements. Fluorescence in situ hybridization (FISH) using chromosome specific α-satellite and whole chromosome-specific painting probes verified the hyperdiploid karyotype, and confirmed the origin of the unknown markers and rearrangements more reliably than would be possible using conventional cytogenetic techniques.

Macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) constitutes a distinct entity characterized by prenatal overgrowth, macrosomia, hemihypertrophy, macrocephaly, nonobstructive hydrocephaly, frontal bossing, hypotonia, developmental delay, generalized or facial capillary malformation with upper philtral nevus flammeus and cutis marmorata, joint hypermobility, loose skin, toe syndactyly, and postaxial polydactyly. All but one of the cases reported previously had benign clinical courses without showing an increased risk of early infant death. We describe three additional cases with poor clinical outcomes including severe postnatal growth failure, intractable cardiac arrhythmia in two cases, and sudden infant death in two cases. Arrhythmia has not been described previously as one of the symptoms of M-CMCT. Patients with M-CMTC associated with severe postnatal growth failure and arrhythmia may constitute a distinct clinical subtype of M-CMTC with an increased risk of life-threatening episodes or sudden death. Recognizing this clinical subtype of M-CMTC is important to prevent these serious potential complications.

OBJECTIVE Familial glucocorticoid deficiency (FGD) has frequently been associated with tall stature in affected individuals. The clinical, biochemical and genetic features of five such patients were studied with the aim of clarifying the underlying mechanisms of excessive growth in these patients. PATIENTS AND METHODS Five patients with a clinical diagnosis of FGD are described in whom the disorder resulted from a variety of novel or previously described missense or nonsense mutations of the ACTH receptor (MC2-R). All patients demonstrated excessive linear growth over that predicted from parental indices and increased head circumference. RESULTS Growth hormone and IGF-I-values were normal. Growth charts suggest that the excessive growth is reduced to normal following the introduction of glucocorticoid replacement. A characteristic facial appearance including hypertelorism, marked epicanthic folds and prominent frontal bossing was noted. CONCLUSIONS These findings indicate that ACTH resistance resulting from a defective ACTH receptor may be associated with abnormalities of cartilage and/or bone growth independently of the GH–IGF-I axis, but probably dependent on ACTH actions through other melanocortin receptors.

OFD syndrome is a group of at least nine disorders that overlap substantially in their physical abnormalities. Although many different malformations are seen in this syndrome, consistent findings include oral anomalies, particularly cleft lip or palate or both, facial anomalies, such as hypertelorism, micrognathia, frontal bossing, or facial asymmetry, and digital anomalies. Other frequent anomalies include central nervous system and genitourinary tract abnormalities. 1,2 Mental retardation is also commonly found in OFD syndrome, type I. 3 We present a case of OFD syndrome, type I, diagnosed in a second trimester fetus.

We describe a girl with a severe progressive type of osteogenesis imperfecta, in association with multisutural craniosynostosis, growth failure, and craniofacial findings including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. Collagen analysis was normal. These features are consistent with the diagnosis of Cole-Carpenter syndrome. This report provides further evidence for the existence of this rare genetic entity.

SPONASTRIME (SPOndylar and NAsal changes, with STRIations of the MEtaphyses) dysplasia is a rare, autosomal recessive bone disorder first described by Fanconi et al. [1983: Helv Paediatr Acta 38:267-280]. Radiographic findings include abnormal vertebral bodies with age-dependent changes, and striations of the metaphyses, scoliosis, and retarded ossification of the carpal bones. Physical features include severe short stature, lumbar lordosis, midface hypoplasia, frontal bossing, and a depressed nasal root. To date, 12 patients from 6 families have been reported. Four additional patients have been reported with a variant of this condition, which includes mental retardation. We report on an 11-year-old boy with features consistent with SPONASTRIME dysplasia. Height was 106.1 cm (-6 SD). He had a coarse appearing face with a depressed nasal bridge, short, upturned nose, and midface hypoplasia. Intelligence was normal. A clinical evaluation at 6 years of age suggested the diagnosis of spondyloepiphyseal dysplasia (SED). However, genetics evaluation at 11 years of age with repeat radiologic studies revealed delayed carpal ossification (-4 to -5 SD), metaphyseal irregularities and striations most notably in the distal femurs and the proximal tibias, lumbar lordosis, narrow interpedicular distances of the lumbar spine, and pear-shaped vertebral bodies. These findings were most consistent with the diagnosis of SPONASTRIME dysplasia, and not SED. Although radiographic findings of SPONASTRIME dysplasia are distinguishable from SED, the physical appearance may be similar. Many bone dysplasias have overlapping radiographic findings and clinical presentation but with different recurrence risks, making genetic counseling a challenge.

We report on a girl with psychomotor retardation, growth retardation, microcephaly, frontal bossing, large ears, small nose, high arched and narrow palate, short neck, and generalized hirsutism. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 7q22-->q31.3 duplication. Comparison with other reported cases shows some resemblance but insufficient to enable us to establish a definite syndrome with specific clinical manifestations. The importance in better analyzing further cases by new molecular cytogenetics techniques is raised.

Few patients with trisomy of the most distal region of chromosome 7q have been described. We report on a familial translocation t(2;7)(q37;q35) leading to trisomy 7q35-->7qter in a child and her paternal uncle and a minimal deletion of distal 2q as demonstrated by FISH with probes located in the chromosome 2q subtelomeric region. The clinical phenotype included macrocephaly and low-set ears, also found in other reported patients trisomic for the distal part of chromosome 7q. Phenotypic findings probably useful for the clinical diagnosis include normal size at birth, large head with frontal bossing, low-set ears of normal shape, small nose and low nasal bridge, feeding difficulties in infancy, and severe neurodevelopmental delay.

We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia complex. The diagnosis was suggested antenatally when obstetrical ultrasonography at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither had had genetic counseling or molecular testing prior to the pregnancy. Antenatal ultrasound study at 29 weeks of gestation showed a large head, very short limbs, and a small chest; the findings were more severe than in achondroplasia or hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of gestation and had rhizomelic shortness of limbs with excess skin creases, large head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness of the long bones and flaring of the metaphyses. She had mild hypoplasia of lungs. Molecular testing showed both the G1138A and the C1620G mutations in FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8 months, she has disproportionate shortness of the long bones and a large head with frontal bossing and a depressed nasal bridge. Her chest remains small, and she is on home oxygen at times of respiratory stress. She has a large gibbus. She is delayed in her motor development and has significant head lag. To our knowledge, there is only one previously published report of achondroplasia-hypochondroplasia complex.

We report on a male newborn infant, a compound carrier of heterozygous mutations in the FGFR3 gene causing achondroplasia and hypochondroplasia. The mother has achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene; the father has hypochondroplasia due to the C1620A (N540K) mutation in the same gene. The fetus was found to carry both mutations diagnosed prenatally by amniocentesis at 17.6 weeks of gestation, following maternal serum screening which showed an increased risk for Down syndrome (1:337). Detailed fetal ultrasound studies showed a large head, short limbs, and a small chest at 22 weeks of gestation. The changes were more severe than those of either achondroplasia or hypochondroplasia. The patient was born by cesarean section at 38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar gibbus, trident position of the fingers, and a narrow chest with a horizontal line of demarcation at the narrowest area of the chest. Skeletal radiographs showed shortness of the long bones and flare of metaphyses. He had respiratory difficulties and was treated with nasal prongs. Seizures developed on day 2 of life and recurred on day 9 and responded to treatment with phenobarbital. Brain computed tomographic scan showed possible grey matter heterotopia, partial agenesis of the corpus callosum, and cortical dysplasia. To our knowledge, there are only two previously published cases of compound heterozygous achondroplasia-hypochondroplasia patients. The diagnosis was confirmed by DNA mutation analysis of the FGFR3 gene in both cases.

We report on a family in which four females and two males in three generations had a previously undescribed brittle bone disorder that was dominantly transmitted through a maternal line. The cardinal manifestations of the disorder comprised dolichocephaly with frontal bossing, hypoplasia of the midface, postpubertal prognathism, micromelic short stature, coarse trabeculae of the entire skeleton, and bone fragility of variable degrees. Mild spondylar modification and iliac hypoplasia were other hallmarks that were recognized in childhood. The proband, a 19-year-old male, was most severely affected with multiple wormian bones in the calvaria, repetitive fractures, intractable bowing of the legs and forearms, and pseudofractures of the long bones with metaphyseal narrowing. His male cousin was next severely affected with angular deformity restricted to the forearm. The four females were much less affected without angular deformity. The mode of inheritance was thus consistent with either an autosomal dominant trait with sex-influence or an X-linked semidominant trait. Histological bone examination in the proband showed atrophy and fibrous degeneration of the lamellar trabeculae and disorganized chondro-osseous junction, which implied that the disorder involved both intramembranous and enchondral ossifications.

Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome.

We report on 3 sporadic cases of in utero onset megalencephaly. Children were born to healthy nonconsanguineous parents after uneventful pregnancies. Head circumferences were just above the 97th centile at birth in 2 patients, 2 cm above the 97th centile in 1 patient, and subsequently increased to 4.5-6.5 cm above the 97th centile at age 5 years. All patients completely lacked motor and speech development and showed very little intellectual progress. There was a distinctive facial aspect with frontal bossing, low nose bridge, and large eyes, but no cutaneous abnormalities and no signs of other organ involvement. Magnetic resonance imaging showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in pachygyric appearance of the cortex. Opercularization was incomplete, and the Sylvian fissures were wide. Somatosensory evoked potentials in 1 patient showed normal latencies of cervical and contracortical potentials but bilaterally increased cortical amplitudes. To the best of our knowledge, no similar case observations have been recorded previously.

We report on a girl with duplication of 6q22.32 → qter and microcephaly, frontal bossing, facial anomalies, and webbed neck. She has congenital heart disease, renal hypoplasia, and hearing loss along with severe developmental delay. Published reports of seven other patients are reviewed and compared. The most frequent anomalies include microcephaly, abnormal face, webbed neck, congenital heart disease, limb contractures, and developmental delay. Am. J. Med. Genet. 78:123–126, 1998. © 1998 Wiley-Liss, Inc.

We describe a brother and sister with severe developmental delay, hypotonia, partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter degenerative abnormalities, macrocrania, frontal bossing, deep-set eyes, and hypertelorism. The brother also had Duane syndrome type II and an ectopic right ureter. The coexistence of these multiple physical and brain abnormalities in a brother and sister suggests a new autosomal recessive syndrome with a slowly progressive course.

Sonographic imaging of the fetal face is important since a number of chromosomal aberrations are associated with facial malformations. In the past, imaging of the fetal forehead and diagnosis of frontal bossing had been based on subjective evaluation using two-dimensional ultrasonography. The purpose of this study was to evaluate quantitatively the fetal forehead using three-dimensional technology to generate normative data throughout gestation. This should allow the objective diagnosis of abnormal growth of the fetal forehead, such as frontal bossing. We also report a case of a fetus with frontal bossing in whom the generated nomogram was applied. A cross-sectional study was performed in 130 normal healthy singleton pregnancies between 16 and 38 weeks' gestation. Using three-dimensional ultrasonography, a line connecting the apex of the philtrum and the nasion was drawn across the anterior forehead, which delineated the area of the forehead for analysis. The forehead length, forehead height, and forehead area under the curve were measured and the forehead index was calculated. A second order polynomial growth function was noted throughout gestation for the forehead length (r = 0.93), forehead height (r = 0.97), and forehead area (r = 0.97). The fetal forehead index remained relatively constant throughout gestation. The results of this study provide normative data of fetal forehead length, width, and area using three-dimensional ultrasonographic technology. Normative dimensions of the fetal forehead developed and presented herein are expected to serve as a basis for the objective assessment of presumed fetal facial abnormalities and may facilitate the detection of the associated syndromes. This is demonstrated in our case report of an achondroplastic fetus in whom all forehead dimensions were above the 95th percentile.

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by hypertelorism, macrocephaly, frontal bossing, broad nasal bridge, palate anomalies, hearing deficits, and mental retardation. The radiographic findings include cranial sclerosis, linear striations in the long bones and iliac wings, small poorly aerated sinuses, scoliosis, and increased bone density. The sensory deficits are disabling, but the condition generally is not life threatening. We describe 4 brothers with the characteristics of OS-CS, 3 of whom have died from more serious complications of the disorder. The mother of these children, and her only daughter, have the mildest phenotype with the typical linear striations in the long bones and macrocephaly. OS-CS is thought to be autosomal dominant with complete penetrance and variable expressivity. Our observations could be consistent with X-linkage, since there is milder expression in the female relatives. In addition, we recognize absent fibulae, malrotation, and omphalocele as new manifestations as well as congenital heart disease.