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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.

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 …

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

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.

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.

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.

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 …

Heterozygous microdeletions of chromosome 2p21 encompassing only the SIX2 gene have been described in two families to date. The clinical phenotype comprised autosomal-dominant inherited frontonasal dysplasia with ptosis in one family. In the second family, conductive hearing loss was the major clinical feature described; however, the affected persons also had ptosis. Here, we present a large family combining all three predescribed features of SIX2 gene deletion. The phenotype in four affected family members in three generations consisted of bilateral congenital ptosis, epicanthus inversus, frontonasal dysplasia with broad nasal bridge and hypertelorism, frontal bossing and large anterior fontanel in childhood, narrow ear canals, and mild conductive hearing loss with onset in childhood. Thus, the phenotypic spectrum of SIX2 haploinsufficiency is widened. Moreover, 2p21 microdeletions with SIX2 haploinsufficiency appear to lead to a recognizable phenotype with facial features resembling blepharophimosis-ptosis-epicanthus inversus syndrome.

Objective: To describe the clinical characteristics and complications observed in tuberculous meningitis (TBM) patients with hydrocephalus who had undergone fluid diversion management. Methods : This was a cross-sectional descriptive observational study involving 28 TBM patients with hydrocephalus aged 0–5 years who had undergone ventriculoperitoneal shunt or extraventricular drainage in the period of July 2011 to July 2016 in Dr. Hasan Sadikin General Hospital, Bandung. Age, gender, head circumferences, nutritional status, and classical characteristics such as sunset eye, frontal bossing, cracked pot sign, venectation as well as complications such as infection, phlebitis, and exposed shunt documented in the hospital medical records were analyzed. Result : The study discovered that infant group was predominant (21/28). Some of the patients had macrocephalus (7/28) and 18 had good nutrition status (18/28). There were 4 patients with frontal bossing characteristics (4/28) and almost none was found with others classic hydrocephalus characteristics. This study found no complication such as infection, phlebitis, and exposed shunt in TBM patients with hydrocephalus who had undergone fluid diversion therapy in Dr. Hasan Sadikin General Hospital, Bandung. Conclusion: One of the most dominan characteristics of TBM patients with hydrocephalus is frontal bossing. Tuberculous meningitis patients with hydrocephalus in our center did not show any fluid diversion-related complications such as infection, phlebitis, or exposed shunt. Keywords: Tuberculous meningitis, hydrocephalus, fluid diversion DOI: 10.15850/ijihs.v6n1.1048

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare multisystemic autosomal dominant disorder typically presenting with cutaneous basal cell carcinomas, multiple keratocysts, and skeletal anomalies. NBCCS is caused by heterozygous mutations in the PTCH1 gene in chromosome 9q22, in the PTCH2 gene in 1p34, or the SUFU gene in 10q24.32. Here, we report on an 18-month-old boy presenting with medulloblastoma, frontal bossing, and multiple skeletal anomalies and his father who has basal cell carcinomas, palmar pits, macrocephaly, bifid ribs, calcification of falx cerebri, and a history of surgery for odontogenic keratocyst. These clinical findings were compatible with the diagnosis of NBCCS, and a novel mutation, c.1249delC; p.Gln417Lysfs*15, was found in PTCH1 causing a premature stop codon.

Gorlin-Goltz syndrome is a rare multisystemic disease inherited in an autosomal dominant pattern. It is characterized by numerous basal cell carcinoma of the skin, jaw cysts, and skeletal anomalies such as frontal bossing, vertebral anomalies, palmoplantar pits, and falx cerebri calcification. There is a tendency to tumors including medullablastoma, fibroma, rabdomyoma, leiomyosarcoma etc.. The diagnosis is based on major and minor clinical and radiologic criteria. Early diagnosis and treatment are of utmost importance in reducing the severity of long-term sequelae of this syndrome. In this article, we present a 15-year-old boy who was admitted to our clinic with brown-black papules and plaques on his scalp and was thought to have Gorlin-Goltz syndrome. He had a history of medulloblastoma that was treated with surgical resection followed by cranial radiotherapy and unilateral retinoblastoma. We present this case, because association of Gorlin-Goltz syndrome and retinoblastoma has not been described previously in the literature and we aimed to draw attention to radiation-induced basal cell carcinomas.

The bossed forehead in patients with scaphocephaly often leads to a high hairline. A new technique to improve the aesthetic outcome of patients undergoing scaphocephaly correction is described. Sixteen patients with scaphocephaly and having a high hairline due to frontal bossing who underwent scaphocephaly correction by subtotal or total vault remodeling were analyzed. The median age at surgery was 18 months. The mean distance between the nasofrontal suture and the hairline was preoperatively 70 mm (range 58-91). An obvious lowering of the hairline could be achieved in all 16 patients. The mean postoperative distance nasofrontal suture to hairline was 59 mm (range 50-73). There were no complications associated with the technique. The hairline lowering technique is a useful addition to vault remodeling techniques and can improve the postoperative aesthetic appearance considerably. The authors recommend this technique in scaphocephaly patients, who present with a high hairline.

Summary Background Spring-assisted cranioplasty (SAC) has become an accepted treatment for patients with sagittal craniosynostosis; however, the early effects of springs on skull dimensions have never been assessed with objective measurements in the literature. The present study evaluated the changes in skull dimensions and intracranial volume (ICV) during the first 3 months after SAC for sagittal synostosis. Methods Sixteen patients with sagittal synostosis underwent SAC. The cephalic index (CI) and the distance between the spring foot plates were chronologically measured until spring removal at 3 months. Pre- and post-treatment CT scans available for 6 patients were used to assess changes in head shape. Thirteen patients underwent objective aesthetic assessment using pre- and post-operative photographs. Statistical analysis was performed using the linear mixed model for chronological data, t-test statistics for normative data comparisons and Wilcoxon's signed rank test for non-parametric data. Results For scaphocephalic patients, pre-operative and post-operative CIs were 0.70 and 0.74 ( p = 0.001), respectively. Cranial widening towards normative values was observed ( p = 0.0005). A continuous expansion in the distance between the spring foot plates was observed over the treatment period. Frontal and occipital angles were not affected by SAC despite apparent clinical improvements in frontal bossing and occipital prominence. CT analysis demonstrated relative reduction in the anterior cranial volume ( p = 0.01) and relative expansion of the superior occipital volume ( p = 0.03). Conclusions Spring expansion was most marked in the hours following spring insertion. The expansion rate reduced to the minimum by day 1 post-operatively. Clinical benefits of SAC resulted from an increase in the bi-temporal width that camouflaged the frontal bossing. Improvement in occipital prominence was due to superior occipital volume expansion, allowing the occiput to remodel to a more rounded shape.

Pycnodysostosis is a rare disorder that was first described in 1962; however, it was only in 1996 that the defective gene was discovered, which led to a better understanding of this disease. This study reports and discuss a case of pycnodysostosis. In addition, a search of articles published in PubMed-Medline was performed. The case was a 13-year-old girl who was referred to a private clinic for dental treatment. Clinical examination showed midface hypoplasia, prominent cheeks, a high nasal bridge, beaked nose, spoon-shaped fingers, frontal bossing, open fontanelles and dental alterations, findings compatible with pycnodysostosis. Patients with this disease also suffer from fractures because of bone hardness with almost no elasticity, a fact that requires special care particularly in the case of children and adolescents. The diagnosis of pycnodysostosis is made based on clinical and radiographic findings. Clinicians should be aware of this disorder to provide adequate dental treatment. Key words:Pycnodysostosis, developmental bone disease, imaging diagnosis.

Objective: The concomitant presence of three histopathologically different lesions in the pituitary gland is a rare occurrence. We present a case of a woman with a large pituitary mass composed of a growth hormone–producing microadenoma, lymphocytic hypophysitis, and a Rathke cleft cyst.Methods: The clinical presentation, laboratory data, imaging studies, and pathology report of the patient's hospital course are described.Results: A 35-year-old woman presented with complaints of fever, persistent headaches, and amenorrhea for 1 year. The patient noted snoring, increase in shoe size, and bilateral hand edema for 3 months. Evaluation revealed a suprasellar mass measuring 2.1 × 1.7 × 2.7 cm with an upward mass effect on the optic chiasm. The physical exam revealed frontal bossing, wide-spaced teeth, prognathism, and sausage digits. Hormonal evaluation was consistent with acromegaly. She underwent a transsphenoidal resection of the lesion, and pathology revealed a growth hormone–producing microadenoma, lymphocytic hypophysitis, and a Rathke cleft cyst.Conclusion: Reports have identified the co-existence of ruptured Rathke cleft cysts with lymphocytic hypophysitis, the presence of Rathke cleft cyst with growth hormone–producing pituitary adenomas, and lymphocytic hypophysitis with growth hormone–producing adenomas. However, we are not aware of any reports of the presence of these three lesions in a single pituitary.Abbreviations: IGF-1 = insulin-like growth factor 1; MRI = magnetic resonance imaging

A 1-month-old full-term female was transferred to our facility from an outside hospital for further evaluation. Pregnancy was complicated by maternal diabetes, and birth weight was 4.1 kg. She was prenatally diagnosed with hypoplastic left heart syndrome and omphalocele. Postnatally, she was found to have cleft lip and palate, two natal teeth, choanal atresia, bilateral clubfeet, and imperforate anus. Physical examination was notable for short limbs and broad, apparently duplicated distal phalanx of digits 1–2 of both hands (Fig. 1). Her facial dys-morphology included frontal bossing, malar hypoplasia, flat nasal bridge, hypertelorism, anteverted nares, and full cheeks (Fig. 2). Imaging was notable for normal-appearing uterus but no gonadal tissue on pelvic ultra-sound, as well as bifid distal phalanges of the bilateral first and second digits on hand radiographs (Fig. 3). Of her various dysmorphic features, we found her duplicated distal phalanges to be the most unique and striking feature, and searched the literature extensively for reports of similar cases, but found none at the time. Her clinical course was marked by cardiorespiratory failure requiring chronic mechanical ventilation, and she ultimately underwent tracheostomy. Throughout her life, she was dependent on tube feeding, ultimately requiring gastrostomy placement. The course was further complicated by pulmonary hypertension and apnea. She expired at 7 months of age because of apnea of unclear etiology. Family history was unremarkable.

Endoscopic approaches to the supraorbital nerve for migraine surgery has been shown to be superior to direct transpalpebral approaches. This modification to the endoscopic approach, with the use of a D-knife blade, can be employed in patients with a long forehead or severe frontal bossing, which may normally lead to difficult access and visualization of the supraorbital foramen.

Basal cell nevus syndrome (BCNS), also known as Gorlin-Goltz syndrome, is a rare autosomal dominantly inherited disorder characterized by the development of basal cell carcinomas (BCCs) from a young age, multiple keratocysts, palmar and/or plantar pits, calcification of falx cerebri, and family aggregations. Other criteria are skeletal anomalies, frontal bossing, cardiac and ovarian fibromas, medulloblastoma, glaucoma, and cleft lip/palate. The disorder is caused by an alteration of the sonic hedgehog signaling pathway, which results in constitutive activity and tumor cell proliferation. Some germline pathogenic variants of these genes, including PTCH1 and SUFU, have been found and are responsible for clinical heterogeneity. Only 2 case reports have described the occurrence of melanoma in patients with BCNS, but neither reported the occurrence of collision lesions [1,2]. Here we present clinical, dermoscopic, and histological features of a collision tumor of BCC and in situ melanoma in a patient with multiple BCCs and BCNS.

Histiocytosis-lymphadenopathy plus syndrome (H syndrome) is caused by mutations in the SLC29A3 gene that result in histiocytic infiltration of numerous organs. Patients suffering from this disorder can be easily mistaken for similar conditions such as Muckle–Wells syndrome. We present a 9.5-year-old boy, who is the offspring of a consanguineous marriage. He suffered from sensorineural hearing loss, dark hyperpigmented indurated dry areas on the medial thighs sparing the knees with hypertrichosis on the affected areas, and areas of hypopigmentation on the abdomen. The patient displayed mild dysmorphism including frontal bossing, synophrys, bilateral proptosis (with normal thyroid function), thick eyebrows, flat nose, long philtrum, and pectus excavatum. Formal intelligence testing showed that he was a slow learner. Laboratory findings included elevated serum amyloid-A, erythrocyte sedimentation rate, and total proteins in urine tests. Complete blood count showed mild microcytic hypochromic anemia. The molecular analysis was crucial to confirm the provisional clinical diagnosis. H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect many organs and can be mistaken for other conditions. Our patient's description may expand the phenotype of H syndrome, as areas of hypopigmentation were observed on the abdomen. Molecular analysis of SLC29A3-related diseases is essential to highlight the variability and increase the awareness of H syndrome aiming for early diagnosis and proper treatment.

Çalışmada 24 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. Objective: Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods: Here we present nationwide initial and follow-up data on HR. Results: From 24 centers, 166 patients were included in the study. Genetic analysis (n = 75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7 +/- 2.4 years. During the first 3-years of treatment (n = 91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p > 0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year Pill was higher. However, higher treatment doses of phosphate and calcitriol were Found in the NC group. Conclusion: HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

We describe a three-year-old male child who presented to the pediatrics out-patient department with a history of decrease in appetite, generalized weakness, on and off loose motions for one year, inability to walk and sit for eight months with a loss of neck holding for 14 days. On examination, the patient had a classic frog-shaped leg posture. X-rays of chest, skull, pelvis and long bones were performed which showed osteopenic bones, frontal bossing and multiple microfractures, which were classic for osteogenesis Imperfecta but the child did not have other salient features such as blue sclera, otosclerosis, and respiratory difficulty. The patient also had urinary complaints due to which ultrasound of kidney ureters and bladder (KUB) was performed, which showed bilateral renal calculi and grade 2 renal parenchymal changes. This case report illustrates the evaluation of the child with osteogenesis imperfecta, as well as the unique association of renal osteodystrophy and gastroenteritis with it.

A 26-month-old boy was admitted because of recurrent fever, generalized erythematous rash, and joint pain. The fever persisted, and the joint pain waxed and waned. The combination of fever, erythematous rash, and joint pain suggested that the patient suffered from a childhood chronic inflammatory illness such as systemic juvenile idiopathic arthritis (sJIA) or chronic infantile neurological cutaneous and articular syndrome (CINCA, alternatively called neonatal-onset multisystem inflammatory disease or NOMID). However, neither of the conditions could explain the unique clinical features and the extraordinary laboratory findings seen in this patient. The patient had characteristic facial features such as flat nasal bridge, frontal bossing, and prominent edema of the eyelids. Marked hepatomegaly was noted, but the spleen was absent. Unlike most of patients with asplenia, this patient did not have any form of congenital heart disease. His brother and sister were healthy. The mother had experienced two intrauterine fetal deaths.

Thanatophoric dysplasia (TD) is the most frequent sporadic lethal skeletal dysplasia with an incidence about 1 in 17.000–50.000 births. Diagnosis of TD can made at prenatal period by ultrasound and immediately after birth based on clinical examination, radiologic studies, histopathology and molecular analysis. Thanatophoric dysplasia is subdivided in two dinstinct phenotypes: 1) Thanatophoric dysplasia type 1 (TD1) is characterized by curved ‘‘telephone receiver’’ femora and mild craniosynostosis or 2) Thanatophoric dysplasia type 2 (TD2) includes straight femora and cloverleaf skull. Girl baby was born from 44 years old female with 35th weeks of gestation (WOG) with non-consanguineous marriage. The patient looked lethargic accompanied with rapid breathing with chest indrawing. On examination the patient looked dysmorphic, large head with frontal bossing without clover leaf skull, upper and lower limbs were extremely short. Babygram showed head was large, thoracic cavity was small and narrow, the ribs were short, and “telephone receiver” like curved femora was noted. Mutational analysis confirmed a heterozygous allele p.Tyr373Cys mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. The patient was diagnosed with TD1. The general condition and respiratory distress did not improve and the patient was died on the sixteenth days of hospitalization. Thanatophoric dysplasia type 1 was rare disease and lethal case. The diagnosis based on clinical examination, radiologic studies, histopathology and molecular analysis. Lethality in thanatophoric dysplasia is caused mainly by respiratory distress due to a narrow thorax.

Primary delayed onset craniosynostosis is a rarely reported phenomenon. The unique case of a 2-year-old boy who had computed tomography (CT) scans performed 20 months apart demonstrating the post-gestational development of sagittal suture craniosynostosis is presented. The otherwise healthy male initially presented to the emergency department at age 7 months with soft tissue swelling over his left parietal region secondary to a fall. A CT scan revealed a possible left parietal skull fracture without intracranial pathology and patent cranial sutures with a normocephalic calvarial configuration. Twenty months later, his paediatrician referred the boy to the craniofacial service for evaluation of progressive dolichocephaly. A new CT scan showed complete fusion of the sagittal suture with resultant biparietal narrowing, frontal bossing, and occipital prominence. The patient subsequently underwent uncomplicated frontoparietal craniotomy with calvarial vault reconstruction. Prior reports in the literature of cases of non-syndromic primary delayed onset craniosynostosis all lack 'pre-synostosis' CT imaging that proves post-birth patency of the cranial sutures. This case report documents CT demonstrating true primary delayed onset craniosynostosis.

Cleidocranial dysplasia (CCD) is a congenital autosomal dominant syndrome characterised by dental and osseous dysplasia that leads to multiple dental and craniofacial anomalies. Two-thirds of CCD cases are associated with mutations of the runt-related transcription factor 2 (RUNX2) gene which codes for a transcription factor that is responsible for differentiation of osteoblasts and osteoclasts and skeletal development. Multiple mutations have been identified in the Runx2 gene, primarily clustered in the Runt domain. Other genes such as CCAAT/enhancer-binding protein beta (Cebpb) and T-box transcription factor TBX1 (Tbx1) are under investigation. There are multiple clinical and radiological signs of CCD, e.g. brachycephaly, frontal and parietal bossing, open sutures and fontanelles, delayed closure of fontanelles, kyphosis, narrow sloping shoulders, multiple wormian bones, and delayed mineralisation of the skull. Although the signs present themselves in varying degrees, certain signs such as supernumerary teeth, frontal bossing, hypoplastic maxilla, and prognathic mandible are characteristic. However, many of them may not appear before the growth spurt in all cases. Early identification of CCD, especially prenatal ultrasound diagnosis, has a better prognosis as early orthodontic intervention can be commenced. Apart from clinical and radiographic analysis, identification of a RUNX2 mutation can serve as a diagnostic aid in families with a history of CCD. However, it is important to understand that only two-thirds of the people with CCD have RUNX2 mutation, so genetic analysis will not be of use in people without the mutations.

We present a family case series with 10 individuals having nevoid basal cell carcinoma syndrome (NBCCS) with a 10-year follow-up. All articles published in the literature between 1967 and 2011 on familial Gorlin-Goltz syndrome in any language were surveyed to determine the mapping of cases per country of occurrence of this disease. All patients in the present series were presented with calcification of the falx cerebri, mild hypertelorism, and frontal bossing. Odontogenic keratocystic tumors, palmar and plantar pits, and multiple basal cell carcinomas occurred in 90, 40, and 20%, respectively, of the patients. One of the patients died of skin cancer. Diagnosis of odontogenic keratocyst tumors was confirmed by histopathological examination. NBCCS is a rare autosomal dominant cancer predisposition syndrome; it is important to recognize it when a patient has multiple odontogenic keratocyst tumors because life-long monitoring is essential for patient management.

Odontogenic keratocysts (OKCs) may occur in two different forms, either as solitary (nonsyndromic OKCs) or as multiple OKCs (syndromic OKCs). Multiple OKCs usually occur as one of the findings in Gorlin-Goltz syndrome with other features such as skin carcinomas and rib, eye, and neurologic abnormalities. We report a rare case of Gorlin-Goltz syndrome in a 20-year-old male patient who presented with a slow growing swelling on lower right and left back teeth region since 2 months. Apart from these, other findings were frontal bossing, depressed nasal bridge, ocular hypertelorism, prominent supra orbital ridge, and mild mandibular prognathism. Excision was done and microscopic study revealed OKC and the follow-up could not be carried out for the complete management. We also presented a review of its pathogenesis, criterion, and differences between syndromic and nonsyndromic OKCs and suggest to thoroughly examine any patient who presents with multiple OKCs to rule out syndromic variety.

Purpose: The 1p36 deletion syndrome is a microdeletion syndrome characterized by developmental delays/intellectual disability, craniofacial dysmorphism, and other congenital anomalies. To date, many cases of this syndrome have been reported worldwide. However, cases with this syndrome have not been reported in Korean populations anywhere. This study was performed to report the clinical and molecular characteristics of five Korean patients with the 1p36 deletion syndrome. Methods: The clinical characteristics of the 5 patients were reviewed. Karyotyping and multiplex ligation-dependent probe amplification (MLPA) analyses were performed for genetic diagnoses. Results: All 5 patients had typical dysmorphic features including frontal bossing, flat right parietal bone, low-set ears, straight eyebrows, down-slanting palpebral fissure, hypotelorism, flat nasal roots, midface hypoplasia, pointed chins, small lips, and variable degrees of developmental delay. Each patient had multiple and variable anomalies such as a congenital heart defect including ventricular septal defect, atrial septal defect, and patent duct arteriosus, ventriculomegaly, cryptorchism, or hearing loss. Karyotyping revealed the 1p36 deletion in only 1 patient, although it was confirmed in all 5 patients by MLPA analyses. Conclusion: All the patients had the typical features of 1p36 deletion. These hallmarks can be used to identify other patients with this condition in their early years in order to provide more appropriate care.

A phenotype of an individual is resulted from an interaction among variants in several genes. Advanced molecular technologies allow us to identify more patients with mutations in more than one genes. Here, we studied a Thai woman with combined clinical features of Marfan (MFS) and Beals (BS) syndromes including frontal bossing, enophthalmos, myopia, the crumpled appearance to the top of the pinnae, midface hypoplasia, high arched palate, dermal stretch marks, aortic enlargement, mitral valve prolapse and regurgitation, aortic root dilatation, and progressive scoliosis. The aortic root enlargement was progressive to a diameter of 7.2 cm requiring an aortic root replacement at the age of 8 years. At her last visit when she was 19 years old, she had moderate aortic regurgitation. Exome sequencing revealed that she carried the c.3159C > G (p.Cys1053Trp) in exon 26 of FBN1 and c.2638G > A (p. Gly880Ser) in exon 20 of FBN2. The variant in FBN1 was de novo, while that in FBN2 was inherited from her unaffected mother. Both genes encode for fibrillins, which are essential for elastic fibers and can form the heterotypic microfibrils. Two defective fibrillins may synergistically worsen cardiovascular manifestations seen in our patient. In this study, we identified the fourth patient with both MFS and BS, carrying mutations in both FBN1 and FBN2.

Hay-Wells syndrome or ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome is a rare form of ectodermal dysplasia. It is an autosomal dominant disorder with various congenital abnormalities involving the skin, hair, teeth, nails, and sweat glands. We report a case of a 7-year-old boy who presented with scaly lesions all over the body that was noticed since birth. The child had scalp erosions and fusion of the eyelids at birth. The child even had patchy scaring alopecia with scaling over the vertex, decreased sweating, and poor formation of nails since birth. We also noted frontal bossing in the child. Epiphora and sparse eye lashes were noted in both eyes. Ear-nose-throat examination revealed rudimentary bifid uvula, aural polyp in the right ear, and abnormal dentition. In view of these clinical signs and symptoms, we arrived at a clinical diagnosis of ankyloblepharon-ectodermal dysplasia-cleft palate (AEC). Due to recurrent scalp pyodermas and seborrheic dermatitis in infancy, the child was suspected and confirmed to have selective immunoglobulin A (IgA) deficiency. We report this case in view of its rare association, i.e., AEC, with selective IgA deficiency.

3-M syndrome is a rare autosomal recessive growth disorder characterized by severe growth retardation, low birth weight, characteristic facial features, and skeletal anomalies, for which three causative genes (CUL7, OBSL1, and CCDC8) have been identified. We herein report two Korean siblings with 3-M syndrome caused by two novel OBSL1 mutations, and describe the effect of a combined treatment with growth hormone (GH) and a gonadotropin-releasing hormone (GnRH) agonist. A 7-year-old girl with short stature (−3.37 standard deviation score, SDS) and breast budding presented with subtle dysmorphic features, including macrocephaly, frontal bossing, a triangular face, prominent philtrum, full lips, a short neck, and fifth-finger clinodactyly. GnRH stimulation test revealed a pubertal pattern and advanced bone age of 8 years and 10 months. Her older sister, aged 10 years and 9 months, had experienced an early menarche, and had an advanced bone age (13.5 years) and predicted adult height of 142 cm (−4.04 SDS). Targeted exome sequencing identified that the siblings had two heteroallelic mutations in OBSL1. Both siblings underwent a combination therapy with GH and a GnRH agonist. A height gain was noted in both siblings even after short-term treatment. To fully elucidate the effects of the combined therapy, a larger cohort should be analyzed following a longer treatment period. However, such an analysis would be challenging due to the rarity of this disease.

In this study, the authors aimed to describe orocraniofacial features and to suggest orthodontic-surgical managements in achondroplasia, based on a literature review. The authors focused on skeletal and dentoalveolar malocclusion in order to highlight the place of orthognathic surgery, based on our experience of 3 patients. Maxillary hypoplasia in achondroplasia typically results in an Angle class III malocclusion with an anterior open bite. The other orocraniofacial features include enlarged calvarium, prominent forehead and frontal bossing, midface hypoplasia, elongated lower face and saddle-shaped nose due to lack of development of the nasomaxillary complex.All our patients had a typical facial appearance but each of them had their own particularities regarding medical history and severity of the dentoskeletal dysmorphosis. Two of them were successfully treated by orthognathic surgery; the other declined surgical treatment and underwent orthopedic treatment only (anchorage plates). The treatment failure of this 3rd patient raises the question of the efficiency of anchorage plates in achondroplasia. In the light of the literature and our results, the authors conclude the need for personalized management based on age, medical history, severity of the dentoskeletal dysmorphosis, functional and/or esthetic disorders, and the patient's needs and requests. In any patient, orthodontic management should be initiated at an early age, and orthognathic surgery modalities should be personalized and adapted to each situation.

By definition, about 2.5% of children show a short stature due to several causes. Two clinical conditions are characterized by serum IGF-I low levels, idiopathic GH deficiency (IGHD), and GH insensitivity (GHI), and the phenotypic appearance of these patients may be very similar. We studied two children with short stature and similar phenotypes. *e first case showed frontal bossing, dollface, acromicria, and truncal obesity, with a GH peak