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Purpose Mowat–Wilson syndrome (MWS) is a rare complex malformation syndrome which is characterized by typical facial dysmorphism, moderate to severe intellectual disability, global developmental delay, and multiple congenital anomalies. Here, we summarize the clinical characteristics and gene mutation analysis of a Chinese boy with MWS. Patients and Methods The clinical features of the patient were monitored. DNA extracted from peripheral blood was subjected to sequencing analysis. Then, the whole-exome sequencing was performed. Results A novel deletion mutation (c.1137_1146del TAGTATGTCT) was identified in exon 8 of the ZEB2 gene. The deletion mutation was predicted to produce a truncated protein (p.S380Nfs*13), resulting in haploinsufficiency. The patient presented with short stature, microcephaly, congenital heart defects, cryptorchidism, corpus callosum agenesis, global developmental delay, and intellectual disability. Furthermore, he demonstrated bilateral sensorineural hearing loss. This manifestation is less common in MWS. It is first reported in Chinese patients with MWS. Clinical follow-up showed that the facial features of MWS developed with time. The facial features of the patient were not obvious except for the uplifted ear lobes at the age of 3 months. At the age of 22 months, the facial characteristics of the patient included ocular hypertelorism, frontal bossing, rounded nasal tip, sparse eyebrows, prominent chin, widely spaced teeth, and uplifted ear lobes with a central depression. Conclusion A novel deletion mutation of the ZEB2 gene was identified. This work contributes to expanding the mutation spectra of MWS. Our results may reflect the variability of the phenotype in MWS., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/42u1gY-Rn7Y

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.

A term 2,535-g female infant is born to a 26-year-old primigravida who is in a non-consanguineous relationship at 37+0 weeks of gestation via cesarean section for breech presentation. Pregnancy complications include nonsevere preeclampsia. Prenatal laboratories, course, and family history are unremarkable other than maternal tobacco use and prior cocaine and heroin use. The neonate’s Apgar scores are 4, 7, and 10 at 1, 5, and 10 minutes, respectively. Physical examination reveals an appropriate-for–gestational age female neonate with frontal bossing, micrognathia, sunken eyes, inverted nipples, mild respiratory distress, and severe hypotonia. The neonate is admitted to the NICU for respiratory distress requiring continuous positive airway pressure. She continues to have desaturations and frequent emesis, prompting a sepsis evaluation with unremarkable findings. Head ultrasonography on day 3 after birth suggests mild cortical atrophy with extra-axial cerebrospinal fluid space expansion in the right parietal parasagittal space. Brain magnetic resonance imaging (MRI) demonstrates mild bilateral parietal and cerebellar atrophy, and repeat MRI on day 8 after birth shows hypoplasia of posterior parietal lobes, inferior vermis, and left transverse sinus as well as buphthalmos. Eye examination shows mature, hypoplastic optic discs. Throughout the hospitalization, she continues to require nasal cannula for desaturations and bradycardic …

Background. We describe a case of an infant with Arnold-Chiari Malformation Type II (ACM-II) who was born with lumbosacral myelomeningocele, hydrocephalus, and primary congenital glaucoma (PCG) together with dysmorphic features (scaphocephaly, frontal bossing, hypotelorism, entropion, and flat nasal bridge), which according to our knowledge, is a combination that has yet to be described in literature. Primary diagnosis. A 2-year-old female who is known to have ACM-II was referred due to abnormal eye examination done in a peripheral hospital that suggested infantile glaucoma in both eyes. Findings. During her last physical exam (postop), she was vitally stable, conscious with good feeding. Ophthalmic assessment revealed buphthalmia, superior paracentral scar, deep anterior chambers (AC), and round pupils with positive red reflex, clear lens, and an IOP of 16, 14 mm Hg, respectively. Neurological exam showed paraparesis and moving upper extremities and has axial hypotonia. Genetic testing showed CYP1B1 gene mutation. Conclusion. The aim of reporting this case is to share the findings in this infant as it may be a new association. The main learning message here is that ACM-II patients may present with certain ocular symptoms, including glaucoma-related ones that may mimic neurological disorders. This report brings information that could alert general practitioners, neurologists, and neurosurgeons. A deeper understanding of this rare disorder may aid the diagnosis of cases with similar characteristic physical findings by referring them to an ophthalmology clinic for further evaluation. Case presentation. A 2-year-old female who is known to have Arnold Chiari Malformation Type II (ACM- II) was referred due to abnormal eye examination done in a peripheral hospital that suggested infantile glaucoma in both eyes. MRI at 3 months of age showed lumbosacral myelomeningocele and hydrocephalus. Genetic testing confirmed a CYP1B1 mutation. These combinations of symptoms were never described in the literature before.

Odontogenic keratocysts (OKCs) may occur in two different forms, either as solitary (non syndromic OKCs) or as multiple OKCs (syndromic OKCs). Multiple OKCs are usually associated with Gorlin–Goltz syndrome with features like skin carcinomas and bifid ribs, eye, and neurologic abnormalities. We report a rare case of Gorlin–Goltz syndrome in a 35-year-old male patient who presented with a swelling in lower left back teeth region since 1 week. Apart from these, other findings observed in the patient were frontal bossing, depressed nasal bridge, ocular hypertelorism, prominent supra orbital ridge, and mild mandibular prognathism. On the basis of clinical and radiological evaluation, Enucleation was planned in all the three quadrants and histopathological evaluation revealed multiple OKC’s. Patient was followed-up multiple times for the duration of six months. This case report highlights the important findings and presentation of a rare case of Gorlin Goltz syndrome along with its review of literature. Keywords: Odontogenic keratocyst, Basal cell carcinoma, Bifid ribs, Gorlin Goltz Syndrome.

Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases associated with NLRP3 gain of function mutations. CAPS associated mutations are found predominantly in exon 3. The objective of this study is to describe a new variant on NRLP3 gene and its phenotype. Case report description of a new NRLP3 pathogenic variant and literature case-based search through INFEVERS database. A 21-year old male who presented multiple tonic–clonic seizures on his 3rd day of life. At age 2, he had recurrent central facial palsy, high fever (40 °C), painful and persistent oral ulcers, abdominal pain, nausea and vomiting, and delayed neuropsychomotor development, with polyarthritis in wrists and knees. Over the years, several symptoms were observed: livedo reticularis, Raynaud’s phenomenon, positive pathergy test, heat allodynia, extremely painful genital ulcers, and sporadic conjunctivitis. Laboratory studies revealed persistently elevated inflammatory markers and serum amyloid protein A (30 μg/l). The genetic panel for autoinflammatory diseases revealed heterozygous mutation in the NLRP3, (c.2068G > C, p.E690Q) with 0% of frequency in the general population. The patient denies rash and did not have frontal bossing or patellar overgrowth. We found a positive familial history on mother and brother, who carried the same mutation. The patient was started on canakinumab which controlled his symptoms. Currently, 241 missense variants in the NLRP3 have been described. We presented a new mutation in exon 3 of the NRLP3 gene in a patient that fulfills clinical criteria for CAPS who had complete clinical response to Canakinumab, supporting the idea that this mutation is pathogenic.

Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. We report the case of a 15-year-old boy with familial short stature, with height of 149 cm (Korean standard deviation score [SDS] of -3.6) and weight of 50.5 kg (-1.48 SDS). He presented with mild midfacial hypoplasia, frontal bossing, a broad chest, and a short neck. The father's and mother's heights were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The patient's bone age was 2–3 years more advanced than his chronological age, and no endocrine abnormalities were detected. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val), in both the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age and should warrant early treatment.

Progeroid syndromes (PS) involve the disorder of early aging. Although survival of progeria syndrome patients is nearly 15 years as per literature, the adult onset progeroid starts manifesting in the third decade. Here, we are presenting a rare case of progeroid at the age of 45 years with mitral regurgitation (MR). The patient has alopecia, dry skin, frontal bossing, up staring eyes with bilateral corneal opacities, prominent nose with parrot beak appearance, thin upper lip, large, low-set ears, periorbital hyperpigmentation, micrognathia, retrognathia, and hyperpigmentation over lower abdomen/both feet and hands. Facial and skeletal manifestation are the major clinical features of the PS; along with the characteristics mentioned above, the patient also had severe eccentric MR. This patient has PS with mitral valve prolapse and severe MR. Most of the features of progeria exist in this patient, which manifested at a younger age. However, the progression of the external features and survival up to 45 years favors PS instead of progeria. Therefore, genetic analysis is mandatory to confirm. We are reporting this case due to the rarity of onset of symptoms within a younger age group; however, the progression of the disease was very slow, which may be a another variant of progeria/PS.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant disorder caused by mutations in the Runx2 gene. The CCD is characterized by frontal bossing, a patent anterior fontanelle, presence of Wormian bones, midface hypoplasia, multiple dental abnormalities, clavicular hypoplasia or aplasia, skeletal abnormalities, and short stature. The aims of this study are to report the phenotypic manifestations of all patients who presented with CCD and to review the multidisciplinary management of these patients. The longitudinal data of patients with a diagnosis of CCD treated at The Australian Craniofacial Unit from 1980 to 2019 were reviewed. Fourteen patients were identified for inclusion in this study. The age at referral to the unit ranged from 1 week old to 49 years old (mean 11.2 years old). All patients had clinical features of frontal bossing, a patent anterior fontanelle, multiple Wormian bones, midface hypoplasia, abnormal dentition, clavicular hypoplasia/aplasia, and normal intellect. Eleven patients had obstructive sleep apnea. Eight patients had positive family history. Speech issues were found in 6 patients and abnormal hearing was found in 4 patients. Seven patients who underwent skeletal survey were found to have skeletal abnormalities. All patients were evaluated and managed by the multidisciplinary team, which consisted of craniofacial surgeons, pediatric dentists, orthodontists, ENT surgeons, pediatricians, clinical geneticists, radiologists, orthopedic surgeons, and social workers. All patients were treated by dentists/orthodontists requiring multiple surgical interventions and orthodontic treatment. Seven patients who had recurrent ear infection underwent ventilation tube insertion. Seven of 11 patients who had obstructive sleep apnea underwent adenotonsillectomy. Four patients underwent orthognathic surgery to correct midface hypoplasia and malocclusion. Two patients had cranioplasty for correction of metopic depressions. The characteristic findings of patients with CCD involving multiple regions of the body should draw clinicians' attention to the need for multidisciplinary management of these patients.

Nevoid basal cell carcinoma syndrome is a rare genetic disorder characterised by multi-organ abnormities such as odontogenic keratocysts in the jaw, skeletal abnormities and multiple basal cell carcinoma etc. Herein, we report a case of nevoid basal cell carcinoma in a 10 year old boy with multiple odontogenic keratocyts of jaw, syndactyly on the left hand, palmar and plantar pits, frontal bossing and whose mother and younger brother also have clinical manifestations of the syndrome. No evidence of basal cell carcinoma seen. Keywords: Nevoid basal cell carcinoma, Gorlin-Goltz syndrome, Odontogenic keratocyst, KCOT, Multiple OKC.

Crouzon syndrome is a rare genetic disorder. We report a rare case of Crouzon syndrome in a very young infant with distinct features of craniofacial malformations. A 10-week-old male child presented with features of craniofacial dysostosis with abnormal shape of the skull, proptosis, hypertelorism, curved nose and frontal bossing. Radiological findings revealed a predominant premature fusion of sagittal sutures. The infant had airway obstruction. Features of hydrocephalus, papilledema and optic atrophy were not evident. We chose to manage the symptoms and prevent complications, and the surgery was deferred for later, depending on the degree of malformation and psychological needs. Diagnosis of this rare condition at an early stage can help in preventing the development of complications. A careful follow-up and appropriate surgical intervention can improve the prognosis of this condition, which carries the risk of respiratory complications, poor vision and, in some cases, mental retardation as the age advances.

Isolated growth hormone (GH) deficiency (IGHD) type 2 is a rare autosomal dominant disorder characterized by severe short stature with low GH level. Timely diagnosis is important for optimal results of recombinant human GH (rhGH) treatment and detection of additional pituitary deficiencies in affected relatives. A male child presented at the age of one year with severe, proportionate short stature [-4.9 standard deviation score (SDS)] and with a normal body mass index (-1.1 SDS). Physical examination revealed frontal bossing, midfacial hypoplasia, normal external genitalia and no dysmorphic features. Paternal and maternal heights were -6.1 and -1.9 SDS. Serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 were undetectable and the peak GH concentration by clonidine stimulation test was extremely low (0.18 ng/mL). Brain magnetic resonance imaging showed anterior pituitary hypoplasia. Genetic analysis identified a novel heterozygous mutation (c.291+2T>G) expected to lead to splicing out exon 3 of GH1. rhGH from age 2.4 years led to appropriate catch-up. In conclusion, we identified a novel GH1 gene mutation in an infant with classical IGHD type 2 presentation.

1. Ashley R.B. Bjorklund, MD*,† 2. Tina M. Slusher, MD*,† 3. Abigail Faulman, MD‡ 4. Cynthia R. Howard, MD† 5. Beatrice Odongkara, MBChB§ 1. *Hennepin Healthcare, Minneapolis, MN 2. †University of Minnesota, Minneapolis, MN 3. ‡Children’s Minnesota, Minneapolis, MN 4. §Gulu University/Gulu Regional Referral Hospital, Gulu, Uganda A 12-year-old boy with a history of sickle cell disease (SCD) presents to a government regional referral hospital in Northern Uganda with complaints of feeling ill with fever and a painful lump on his forehead. He also notes pain and swelling of his left upper arm. The fever, forehead lump, and painful swelling of the left arm had been present for at least 2 months. He denies any trauma. On presentation to the hospital he is febrile, tachycardic, and ill appearing. Initial physical examination is remarkable for frontal bossing with multiple tender, fluctuant, round (2- to 3-cm-diameter) lesions over his forehead and scalp; respiratory distress; a prominent systolic murmur; thin limbs; a tender, indurated lesion (approximately 5 × 3 cm) draining purulent fluid on his left upper arm; and no noted focal neurologic deficits. In the emergency department, incision and drainage of the forehead lesion yields scant drainage despite what appears to be a visibly purulent and fluctuant swelling. The fluid obtained is serous and bloody, without overt purulence. There is concern that the lesions may involve more than the subcutaneous tissues, with possible extension to the bone. Laboratory tests show leukocytosis with a neutrophil predominance (white blood cell count, 23,360/μL [23.36×109/L]; neutrophils, 77.5%), thrombocytosis, and anemia (hemoglobin level, 7.7 g/dL [4.78 mmol/L]). Rapid diagnostic testing for malaria is negative. Urine is remarkable for dark coloration without red blood cells on microscopic examination. Cultures from the wound are sent to the laboratory. Radiographs of the cranium (Fig 1) and humerus (Fig 2) are obtained. Figures 1. Radiograph demonstrating lytic lesions of the frontal and parietal bones. Figure 2. Radiograph demonstrating …

3M syndrome is characterized by severe pre- and post-natal growth restriction, typical face, slender tubular bones, tall vertebral bodies, prominent heels and normal intelligence. It is caused by biallelic variants of CUL7, OBSL1 and, more rarely, CCDC8. The aim of this study is to evaluate facial and skeletal findings in 3M patients from neonatal period to adulthood. A total of 19 patients with a median age of diagnosis of 9.2 months were included in this study and were followed for two to 20 years. CUL7 and OBSL1 variants were found in 57.9% and 42.1% of patients, respectively, five of which are novel. Most of patients had triangular face, frontal bossing, short fleshy nose, full fleshy lower lip, transverse groove of rib cage, hyperlordosis and prominent heels. Three new early-diagnostic signs were observed in infants; two were infraorbital swelling of the lower lid and facial infantile hemangioma, both of which became less pronounced with aging. The third was the central tubercle of the upper lip that became more prominent with in time. While slender long bones did not change with aging, the tall vertebral bodies became more prominent radiologically. The mean birth length in patients was −4.3 SDS. Eight patients reached a mean final height of −4.9 SDS. Despite described growth hormone (GH) insensitivity in 3M syndrome, 12 patients either with GH deficiency or with normal GH levels were treated with GH; seven patients responded with an increase in height SDS. This study not only provided early diagnostic signs of the syndrome, but also presented important follow-up findings.

Thanatophoric dysplasia is a lethal form of skeletal dysplasia seen in neonates. The word ‘thanatophoric’ is derived from the Greek word thanatophorus meaning death bringing. Thanatophoric dysplasia results from mutations within the Fibroblast Growth Factor Receptor 3 (FGFR3) gene which is located on chromosome 4p16.3. A female neonate with dysmorphic features such as macrocephaly, frontal bossing, periorbital swelling and depressed nasal bridge was delivered to a 35year old woman. The upper and lower limbs were short with excessive skin folds. A case of female neonate with thanatophoric dysplasia is hereby reported to raise awareness of this condition and to describe the features of thanatophoric dysplasia seen in this patient . Key words: Thanatophoric Dysplasia (TD), Fibroblast Growth Factor Receptor 3 Gene (FGFR3), dysmorphic, macrocephaly

BACKGROUND The need for surgical correction of frontal bossing in patients with sagittal synostosis is currently debated. The authors retrospectively analyzed frontal bossing in patients with isolated, nonsyndromic sagittal synostosis who underwent calvarial remodeling with and without frontal craniotomy and compared with control subjects. METHODS The authors analyzed computed tomography (CT) scans of patients with sagittal synostosis

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.

El síndrome de Pfeiffer es una enfermedad rara de tipo autosómica dominante caracterizada por craneosinostosis bicoronal, hipoplasia medio facial y sindactilia de manos y pies. Se ha descrito 3 fenotipos, siendo el tipo 2 el más severo y que generalmente se diagnostica prenatalmente. Presentamos el primer caso descrito en el Instituto Nacional Materno Perinatal de Lima, Perú, de un feto con hallazgos ultrasonográficos sospechosos de este síndrome, como el cráneo en forma de trébol, ventriculomegalia severa, frente abombada, ojos protruidos y dedos superpuestos, que nació por cesárea y falleció a los 8 días de edad por distrés respiratorio progresivo.

A male infant is born at 37 6/7 weeks' gestation by repeat cesarean delivery to a 33-year-old gravida 2, para 0 mother who had a previous fetal demise at 37 weeks' gestation (etiology unknown; no autopsy performed). For this current pregnancy the mother had regular prenatal care. Gestational diabetes was treated with dietary interventions. The mother is deaf due to childhood meningitis. She has a history of genital herpes simplex virus (HSV), with no active lesions at the time of delivery while receiving suppressive valacyclovir. The delivery is complicated by a nuchal cord and difficult extraction. The infant requires brief positive pressure ventilation. Apgar scores of 8 and 9 at 1 and 5 minutes, respectively, are given. The infant weighs 3,735 g and is noted to have macrocephaly, with a head circumference of 15.8 in (40 cm). His length is 19.7 in (50 cm) and plots at 52%. He has a large open anterior fontanelle and asymmetrical frontal bossing, with prominence of the right forehead. The remainder of his newborn examination findings are normal. At 2 hours after birth he develops intermittent oxygen desaturations associated with arching of his back followed by right-sided shaking. His blood sugar level is 78 mg/dL (4.3 mmol/L). He is placed on 1-L nasal cannula oxygen and is loaded with 20 mg/kg of phenobarbital for suspected seizures. A blood culture is performed, and he is started on ampicillin, gentamicin, and acyclovir. A normal saline fluid bolus is given, and maintenance fluids are initiated at 80 mL/kg per day. The infant is then transferred to a facility that provides a higher level of care. On arrival at our facility he is noted to be hypotonic and requires nasal cannula oxygen at 2 L. The results of his complete blood cell count and comprehensive metabolic panel are …

Cranial index is a widely used 2-dimensional measure of skull form. It has traditionally been calculated as a ratio of the maximal cranial width divided by the maximal skull length. Nevertheless, the points of maximal skull length change dramatically in sagittal craniosynostosis due to variable degrees of frontal and occipital bossing. Therefore, such anatomical changes influence the calculated cranial index. Method This is a retrospective comparative study of 2 methods of measuring cranial index; the traditional method that measures the skull length from glabella to opithcranion versus a modified method that measures the maximal skull length from the most anterior point of the frontal bossing to opithcranion. Cranial indices for 115 patients of radiologically and clinically diagnosed nonsyndromic sagittal craniosynostosis were calculated using both methods. Correlation and Agreements Limits were calculated for comparison between the 2 methods. Results Males constituted 74.8% (n = 86) of the total sample size with the remaining 29 participants identified as female. The mean age of the study participants was 4.8 months (range 8 days-12 months). The 2 methods were strongly correlated (r = 0.94). The Agreement Limits were calculated to be between 4.02% and 0.18%. Conclusion Typical anatomical changes such as variable degrees of frontal and occipital bossing influence the accuracy of cranial index measurement in sagittal craniosynostosis. Traditional method of cephalic index measurement could underestimate the severity of scaphocephaly.

Background Endoscopic suturectomy and helmeting represents a successful first-line surgical treatment for bilateral coronal craniosynostosis. Its effect on cranial morphology has not been previously described. Methods Patients were identified who had bilateral coronal craniosynostosis treated with endoscopic suturectomy and postoperative helmeting at Boston Children's Hospital between 2005 and 2013 and who underwent preoperative and postoperative computed tomography. Two normative patient populations were identified from our trauma registry with computed tomographic scans completed at the same age as our pretreatment and posttreatment scans. Craniometric indices were used to quantify the effect of treatment. Results Twenty-seven patients were identified who underwent bilateral coronal suturectomy. Twelve patients had preoperative and postoperative computed tomographic studies. Eight patients (66.7 percent) were syndromic. The average ages for preoperative and postoperative computed tomographic scan were 1.1 months (range, 0.03 to 2.6 months) and 19.6 months (range, 10.8 to 37.5 months). Thirteen patients with an average age of 1.1 months (range, 0.5 to 1.6 months) were identified as a preoperative control group. Fourteen patients with an average age of 18.5 months (range, 15.5 to 22.9 months) were identified as a postoperative control group. The anterior cranial height stabilized with treatment and the anterior cranial base length increased. The anterior cranial height-to-anterior cranial base length ratio significantly decreased with treatment (p = 0.128). Frontal bossing normalized with endoscopic suturectomy (craniosynostosis versus control: preoperatively, p = 0.001; postoperatively, p = 0.8). Cephalic indices also normalized with treatment (craniosynostosis versus control: preoperatively, p = 0.02; postoperatively, p = 0.13). No cases of hydrocephalus were observed. Conclusion Endoscopic suturectomy and helmeting improves anterior turricephaly and corrects frontal bossing and brachycephaly in patients with bilateral coronal craniosynostosis. Clinical question/level of evidence Therapeutic, IV.

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.

Sagittal craniosynostosis is the most common form of nonsyndromic craniosynostosis.1 In unaffected patients without craniosynostosis, the morphology of the cranium is related to the underlying functional effects of the brain and dura: bones grow and head shape forms in the presence of patent cranial sutures.2 With premature sutural fusion, cranial morphology takes on characteristic shapes corresponding to the particular fused suture(s). Children with sagittal craniosynostosis exhibit varying degrees of scaphocephaly, which may include frontal bossing, an anteriorly displaced vertex, narrowed bi-parietal distance, and a bullet-shaped occiput.3 The effect on head shape is more significant when fusion occurs early in development.2,4 The head circumference typically increases as a result of excessive anomalous anterior-posterior skull growth.5 In all cases of craniosynostosis, surgical treatment is indicated for elevated intracranial pressure (ICP) and/or substantial alterations in normal anatomy and appearance. The risk of elevated ICP in single suture, nonsyndromic sagittal synostosis is estimated to be 10%–20%,6 but reports are inconclusive and often contradictory. Data regarding the probability of neurodevelopmental delay associated with the condition are likewise inconsistent; some suggest up to a 5-fold increased risk for developmental delays and learning deficits in infancy..7–9 Although there are numerous approaches in treating isolated sagittal craniosynostosis, there is currently no consensus among craniofacial surgeons or pediatric neurosurgeons regarding the optimal approach.10,11 Furthermore, the decision whether to operate at all in nonsyndromic patients with sagittal synostosis relies largely on intuition and individual surgical judgment, without objective data to clarify clinical management. Others have investigated similar decision-making processes for other forms of craniosynostosis.12 The goal of this study was to identify factors that prompt in cases of sagittal synostosis surgical intervention. Using a custom-engineered 3D design framework, we developed a novel survey tool to assess practice patterns among pediatric neurosurgeons and pediatric craniofacial surgeons around the world.

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

BACKGROUND: Patients with KBG Syndrome due to ANKRD11 mutations and 16q24.3 microdeletions including ANKRD11 were identified. Classical and most frequent phenotypes include various degrees of intelligence disability (ID), short stature (SS), delayed bone age, macrodontia, distinctive facial features and skeletal anomalies. The variable expressivity of KBG syndrome makes it challenging to establish genotype-phenotype correlations, which also affects further studies for this novel syndrome. We aim to report three unrelated patients with KBG syndrome caused by ANKRD11 gene pathological variants and to evaluate potential associations among ANKRD11 gene variant types, the 16q24.3 microdeletion, and the clinical spectrum of KBG syndrome. METHODS: The genetic etiology of three unreported KBG patients was identified by whole exome sequencing and confirmed via Sanger sequencing. Literature review was conducted to summarize the phenotype-genotype relationship based on three unreported Chinese cases and 186 reported cases. RESULTS: Two pathological variants (c.7407dupC, p.P2530Rfs*61; c.G3046A, p.D1016N) and one reported variant (c.6792dupC, p. P2271Pfs*8) were detected in our patients. Compared with the 16q24.3 microdeletion, patients harboring ANKRD11 gene mutations showed significantly higher frequency of malformations including macrodontia, long philtrum, abnormal eyebrows, widely spaced eyes, anteverted nares, eyelid ptosis, brachydactyly, brachycephaly (P

Pure distal duplications of 7q have rarely been described in the medical literature. The term pure refers to duplications that occur without an accompanying clinically significant deletion. Pure 7q duplications of various segments have previously been reported in the literature; however, pure distal 7q duplications have only been reported in 21 cases. Twenty of these earlier reports described patients who were identified via karyotype and 1 recently by microarray. Cases have also been reported in genomic databases such as DECIPHER and the University of California Santa Cruz genome browser. We have reviewed 7 additional cases with distal 7q duplications from these databases and compared them to 7 previously reported distal 7q duplication cases to uncover common features including global developmental delay, frontal bossing, macrocephaly, seizures, kyphoscoliosis/skeletal anomalies, and microretrognathia/palatal anomalies. In this case, we describe a 4-year-old boy with a 30.8-Mb pure duplication of 7q32.1q36.3. Newly reported features associated with this duplication include intermittent dystonic posturing, increased behavioral irritability, eosinophilic esophagitis, segmental vertebral anomalies, and segmental intermittent limb cyanosis. We highlight the importance of using publicly available databases to describe rare genetic syndromes and to better characterize the features of pure distal 7q duplications and further postulate that duplication of this region represents a recognizable macrocephalic neurodevelopmental syndrome.

The forehead is one of the major determinants of one’s appearance and considered as an esthetic unit because it is a seamless, homogeneous surface of the upper face. Disturbance of this harmony may lead to the appearance of frontal bossing. Various etiologic factors such as craniofacial anomalies or other underlying medical conditions have been attributed to this appearance. Therefore, there have been increasing esthetic concerns of the forehead and demand for contouring surgery over the past few years. Cosmetic surgical techniques are discussed in this chapter with the aim of eliminating the esthetic disharmony caused by frontal bossing.

Background The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up. Methods Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p Results Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups. Conclusions Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points. Clinical question/level of evidence Therapeutic, IV.

Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients. Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

Changes made to the forehead and periorbital region can have dramatic effects in gender-affirmation surgery. Removal of frontal bossing and alteration of orbital shape can result in significant facial feminization. This elective surgical intervention must be safe, reliable, and aesthetically effective. The described technique of frontal and periorbital bone contouring allows for a safe and consistent surgical outcome in properly selected patients. Nuances in specific technical maneuvers in this operation can have profound effects on safety and aesthetic outcomes. In this article, specific points are detailed in text and video describing the senior author's (E.D.R) surgical approach.

Microdeletions within 1q24 have been associated with growth deficiency, varying intellectual disability, and skeletal abnormalities. The candidate locus responsible for the various phenotypic features of this syndrome has previously been predicted to lie in the area of 1q24.3, but molecular evidence of the causative gene remains elusive. Here, we report two additional patients carrying the smallest reported 1q24 deletion to date. Patient 1 exhibited intrauterine growth retardation, shortening of the long bones, frontal bossing, microstomia, micrognathia, and a language acquisition delay. Her mother, Patient 2, displayed a broad forehead and nasal bridge, thick supraorbital ridges, and toe brachydactyly, along with learning disability and language acquisition delay. The microdeletion encompasses a 94 Kb region containing exon 14 and portions of the surrounding introns of the gene encoding dynamin 3 (DNM3), resulting in an in-frame loss of 38 amino acids. This microdeletion site also contains a long non-coding RNA (DNM3OS) and three microRNAs (miR-214, miR-199A2, and miR-3120). Following culture of patient-derived and control fibroblasts, molecular analyses were performed to determine expression levels of genes affected by the heterozygous deletion. Results show decreased expression of DNM3OS and miR-214-3p in patient fibroblasts cultured in an osteogenic induction medium. Overall, our data provide further evidence to support a functional role for non-coding RNAs in regulating the skeletal phenotype, and the potential of a functionally-impaired DNM3 protein causing the non-skeletal disease pathogenesis.

Background Sotos syndrome is caused by a gene deletion with an autosomal dominant pattern of inheritance. The Sotos syndrome was first described by Juan Sotos. Cole and Hughes identified the clinical characteristics of this syndrome. This syndrome is characterized by macrocephaly, frontal bossing, ocular hypertelorism, overgrowth, subdural hygroma, ventricular dilatation, agenesis of the corpus callosum. This syndrome is associated with mutations in NSD 1 (nuclear receptor SET domain-containing protein 1) gene, protein insufficiency, and a 5q35 microdeletion. Sotos syndrome is reported to occur in approximately 1/10,000–15,000 births. Case presentation We present a patient with Sotos syndrome who is harboring a sacral lipoma and tethered cord syndrome and she had growth retardation, frontal bossing and hypertelorism. After a standard approach for tethered cord syndrome, the patient was discharged 3 days after without any additional neurodeficits. Conclusion In the literature, sacral lipoma and tethered cord syndrome with Sotos syndrome have not been published yet.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella that includes a broad range of rare disorders, ranging from isolated digit enlargement to extensive overgrowth of the limbs, abdomen, or brain. One of these disorders is megalencephaly capillary malformation polymicrogyria syndrome (MCAP), which is characterized by cutaneous capillary malformations, megalencephaly, cortical brain malformations, abnormalities of somatic growth with body and brain asymmetry, developmental delay, and characteristic facial dysmorphism. The diagnosis of PROS syndrome is based on the clinical features of a patient and confirmed by a pathogenic variant in one PIK3CA allele in a biopsy of the affected tissue. However, MCAP may be diagnosed by testing a blood or saliva sample. The management of patients with MCAP syndrome includes evaluation after the initial diagnosis, treatment of manifestations, and surveillance for potential complications. To date, there is no curative treatment for patients with MCAP syndrome. Therefore, reporting such cases will help us understand them and thus develop an appropriate treatment for them. Our patient was a 46-month-old boy, who is diagnosed with MCAP syndrome. The diagnosis was based on clinical presentation, imaging studies, and whole-exome sequencing (WES). Clinically, the patient had speech and developmental delay, macrocephaly, joint hyperlaxity, unsteady gait, and subtle dysmorphic facial features. The facial features include low-set ears, frontal bossing, depressed nasal bridge, and bilateral esotropia. MRI studies showed megalocephaly, bilateral perisylvian polymicrogyria, bilateral peri-regional, high T2 signal intensities, and cerebellar tonsil ectopia with crowding of the posterior fossa. Finally, the diagnosis was confirmed by WES, which detected changes in the PIK3CA gene. The patient is on overgrowth protocol for PIK3CA, which includes alpha-fetoprotein and abdominal ultrasound every three months until the age of eight years. To the best of our knowledge, this is one of the first cases of PROS in Saudi Arabia, which illustrates the classical findings of MCAP syndrome. Further studies and investigations on PROS syndrome are needed to aid in making a definitive classification and treatment of such complex and rare diseases.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down‐slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha‐fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype‐phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

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.

A term newborn with macrocephaly, a narrow bell-shaped thorax, and micromelia. ### Prenatal and Birth Histories ### Presentation The infant had multiple congenital anomalies including frontal bossing, macrocephaly, shortened extremities with skin folds, and a narrow, bell-shaped thorax. Parents were counseled regarding the infant’s poor prognosis and futility of care, in view of the clinical presentation. The parents requested resuscitation and further testing. The infant was admitted to the NICU and placed on high-frequency oscillatory ventilation with a mean airway pressure of 14 cm H2O and fraction of inspired oxygen concentration (FiO2) of 1; confirmatory tests were performed based on phenotypic presentation. ### Vital Signs ### Physical Examination

A female neonate is born at 33 weeks of gestation via urgent cesarean section secondary to severe preeclampsia with hemolysis, elevated liver enzymes, and low platelet count syndrome. On examination, her weight is 1.18 kg (1st percentile), length 39.5 cm (5th percentile), and head circumference 27 cm (1st percentile). She is well appearing with white sclera, normal tone, and appropriate reflexes. She has scaphocephaly, a soft skull, proptosis with shallow orbits, low-set ears, swelling of the right wrist, a widened fontanelle, prominent knobs along her ribs, and frontal bossing. Laboratory results are notable for normal serum calcium, low serum phosphorous, elevated parathyroid hormone, low 25-hydroxyvitamin D, elevated 1,25-dihydroxyvitamin D, normal urine electrolytes, and negative findings on New York State newborn screening (Table 1). Radiographs obtained shortly after birth show bony demineralization, metaphyseal flaring particularly at the wrists and knees, metaphyseal fractures, and bilateral rib fractures (Fig). The maternal history is significant for 5 previous miscarriages, nonadherence with taking prenatal vitamins, a diet containing minimal dairy products, and modest dress for religious observance, with limited skin exposure to natural sunlight. The parents are consanguineous. View this table: Table 1. Initial Laboratory Testing Figure. Frontal view of the chest demonstrates bone demineralization, flaring of the metaphyses at the wrist (arrows), and metaphyseal fractures (arrowheads). Bilateral rib fractures are noted (asterisk). Knee films demonstrated …

The purpose of this article is to analyse all cases of thanatophoric dysplasia and document the associated CNS anomalies. A retrospective study of all cases of thanatophoric dysplasia diagnosed in the department of perinatal pathology from January 2009 to December 2016. The various associated findings with due reference to the CNS manifestations were analyzed. During the study period, 7741 foetal autopsies were done, of which 24 (0.31%) were diagnosed to have thanatophoric dysplasia. The brain of one case was autolysed and hence, this had been excluded from this study. Of the 23 cases, 19 were of type 1 (83%) and 4 were of type 2 (17%). CNS anomalies were present in all. In our series, the characteristic findings seen in TD type 1 were enlarged skull, short neck, narrow thorax, protuberant abdomen, severe rhizoacromelic shortening of all four limbs with bowing of lower limbs. Whereas, type 2 manifested with large clover leaf skull with frontal bossing, short neck, short ribs, protuberant abdomen, severe rhizoacromelic shortening of all four limbs. Both the types had their characteristic fetogram findings. Central nervous system anomalies were seen in all 23 cases; which were multiple bilateral clefts seen in the inferior surface of the temporal lobe and medial surface of the occipital lobe. There were no noticeable differences in CNS abnormalities between TD type I and II. Clefting disorders consistently seen in the present series and in other reports calls for attention to be given to cortical malformations of the temporal lobe. This constellation of brain abnormalities needs recognition in fetal imaging and we propose that this should be included in the guidelines for diagnosis of thanatophoric dysplasia.