Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand abnormal calcification type: Further expanding the mutational spectrum and dental findings of three new patients.

Genetic skeletal disorders are clinically and genetically heterogeneous group of disorders that affect the normal development, growth, and maintenance of the human skeleton. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED-SL/AC; MIM# 271665) is a rare autosomal recessive genetic skeletal disorder characterized by distinctive facial features, disproportionate short stature, vertebral, metaphyseal, and epiphyseal abnormalities. This unique phenotype is caused by biallelic loss-of-function variants in Discoidin domain receptor 2 gene (DDR2, MIM# 191311). To date, only 10 pathogenic variants (six missense, two nonsense, one deletion, and one splice site) in DDR2 have been reported in patients with SMED-SL/AC. Dental anomalies related to skeletal dysplasia can include various abnormalities in the number, shape, and position of teeth in the jaw, as well as enamel hypoplasia and dentinogenesis imperfecta. Although abnormal dentition has previously been reported, orodental findings were described in only six patients with SMED-SL/AC. This study aimed to define the clinical, dental, radiological, and molecular findings of three new SMED-SL/AC patients from three unrelated families. Three DDR2 variants, two of which were novel, were detected with the aid of Sanger sequencing. Interestingly, one of the patients was diagnosed with Wilson's disease (WD) during the follow-up, a co-occurrence that has never been reported in patients with SMED-SL/AC so far.

Homozygous Missense Epithelial Cell Adhesion Molecule Variant in a Patient with Congenital Tufting Enteropathy and Literature Review.

Congenital diarrheal disorders (CDDs) with genetic etiology are uncommon hereditary intestinal diseases characterized by chronic, life-threatening, intractable watery diarrhea that starts in infancy. CDDs can be mechanistically divided into osmotic and secretory diarrhea. Congenital tufting enteropathy (CTE), also known as intestinal epithelial dysplasia, is a type of secretory CDD. CTE is a rare autosomal recessive enteropathy that presents with intractable neonatal-onset diarrhea, intestinal failure, severe malnutrition, and parenteral nutrition dependence. Villous atrophy of the intestinal epithelium, crypt hyperplasia, and irregularity of surface enterocytes are the specific pathological findings of CTE. The small intestine and occasionally the colonic mucosa include focal epithelial tufts. In 2008, Sivagnanam et al. discovered that mutations in the epithelial cell adhesion molecule (EpCAM, MIM# 185535) were the genetic cause of CTE (MIM# 613217). More than a hundred mutations have been reported to date. Furthermore, mutations in the serine peptidase inhibitor Kunitz type 2 (SPINT2, MIM# 605124) have been linked to syndromic CTE. In this study, we report the case of a 17-month-old male infant with congenital diarrhea. Despite extensive etiological workup, no etiology could be established before admission to our center. The patient died 15 hours after being admitted to our center in a metabolically decompensated state, probably due to a delay in admission and diagnosis. Molecular autopsy with exome sequencing revealed a previously reported homozygous missense variant, c.757G>A, in EpCAM, which was confirmed by histopathological examination.

Recurrent squamous cell carcinoma and a novel mutation in a patient with xeroderma pigmentosum: a case report.

BACKGROUND: Xeroderma pigmentosum is an extremely serious genetic disorder defined by sensitivity to sunlight, resulting in sunburn and pigment changes. If patients are not completely protected from ultraviolet radiation, xeroderma pigmentosum is characterized by a greatly increased risk of sunlight-induced cutaneous neoplasms. There is no standard therapy for skin cancer of xeroderma pigmentosum. However, immune checkpoint inhibitors were reported to increase response rates and improve outcomes and life expectancy in patients with various cancers, including squamous cell carcinoma in xeroderma pigmentosum. In this paper, we report on a patient with xeroderma pigmentosum from a consanguineous family with recurrent facial chemotherapy-resistant squamous cell carcinoma lesions treated successfully with an anti-programmed cell death protein 1 monoclonal antibody in both relapses. CASE PRESENTATION: A 7-year-old Turkish male was referred to our oncology department for recurring squamous cell carcinoma after local excision of the tumor over his nose. The lesion was a rapidly growing lesion, measuring 8 × 4 cm in size. Physical examination revealed that he also had hemorrhagic crusted plaques and nodules over both eyelids and upper lip, with multiple hypo- and hyperpigmented punctate lesions all over his body. After two more cycles of chemotherapy, progressive disease was noted, and a new lesion on the right eyelid caused blurred vision. Anti-programmed cell death protein 1 antibody treatment was planned with concomitant radiotherapy. He received nivolumab every 3 weeks for 4 months, improving his vision. No new lesions or active complaints have been observed in the current situation, and complete remission has been achieved. On the last admission, the patient was clinically diagnosed with xeroderma pigmentosum. Owing to the condition's genetic heterogeneity, whole-exome sequencing was performed with Ion Proton next-generation sequencing platform, and the c.2250 + 1G>A splice site mutation of the XPC gene was detected in the homozygous state. CONCLUSIONS: The clinical report emphasizes the importance of clinical awareness and crucial early diagnosis of xeroderma pigmentosum and presents a novel causative homozygous c.2250 + 1G>A splice site mutation. Our case proves that next-generation sequencing is an effective method for the rapid diagnosis and determination of xeroderma pigmentosum genetic etiology.

Spondyloepimetaphyseal dysplasia EXTL3-deficient type: Long-term follow-up and review of the literature.

Spondyloepimetaphyseal dysplasia (SEMD) is a group of genetic skeletal disorders characterized by disproportionate short stature, and varying degrees of vertebral, epiphyseal, and metaphyseal involvement of the skeleton. According to the Nosology and classification of genetic skeletal disorders 2019 revision, more than 20 types of SEMD have been identified, and SEMD with immune deficiency, EXTL3 type is one of the newcomers. Affected individuals display variable skeletal abnormalities and neurodevelopmental findings. Liver and kidney cysts have also been reported frequently. Patients may exhibit varying degrees of immune deficiency as well. To date, only 14 patients from 9 unrelated families with SEMD with immune deficiency, EXTL3 type have been reported in the literature. We report a new patient who is currently 15 years old in whom cystic liver lesions were detected in the prenatal period. Disproportionate short stature, mild developmental delay and a T- NK+ B+ immunological profile were detected in the postnatal follow-up. Exome sequence analysis revealed a previously reported homozygous missense variant in exon 3 c.953C > T; p.(Pro318Leu) in EXTL3.

Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features.

Colony stimulating factor 1 receptor (CSF1R, MIM# 164770) encodes a tyrosine-kinase receptor playing an important role in development of osteoclasts and microglia. Heterozygous CSF1R variants have been known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS, MIM# 221820), an adult-onset leukoencephalopathy characterized by loss of motor functions and cognitive decline. Recently, a new phenotype characterized by brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) with biallelic CSF1R pathogenic variants in the etiology has been described. BANDDOS differs from HDLS by early-onset neurodegenerative changes with additional structural brain abnormalities and skeletal findings resembling dysosteosclerosis (DOS). Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS. To date, only a few patients carrying biallelic CSF1R variants have been reported. In this clinical report, we describe three siblings with variable skeletal findings along with neurological symptoms ranging from mild to severe in whom exome sequencing revealed a novel homozygous splice site variant in canonical splice donor site of intron 21 adjacent to an exon, which encoding part of kinase domain of CSF1R along with a review of the literature.

A rare cause of syndromic short stature: 3M syndrome in three families.

3M syndrome is a rare autosomal recessive genetic disorder characterized by severe growth retardation, dysmorphic facial features, skeletal dysplasia, and normal intelligence. Variants in CUL7, OBSL1, and CCDC8 genes have been reported to be responsible for this syndrome. In this study, the clinical and molecular findings of four 3M syndrome cases from three families are presented. All cases had growth retardation, relative macrocephaly, and typical dysmorphic facial features. Their neurological developments were normal. Sequencing of CUL7, OBSL1, and CCDC8 genes revealed two different novel homozygous variants in CUL7 in Families 1 and 3 and a previously reported homozygous pathogenic variant in OBSL1 in Family 2. In conclusion, a comprehensive dysmorphological evaluation should be obtained in individuals presenting with short stature and in such individuals with typical facial and skeletal findings, 3M syndrome should be considered. Our report expands the genotype of 3M syndrome and emphasizes the importance of thorough physical and dysmorphological examination.

Impact of mannose-binding lectin 2 gene polymorphisms on disease severity in noncystic fibrosis bronchiectasis in children.

BACKGROUND: Mannose-binding lectin (MBL) is a complement protein involved in the innate immune system, and is associated with some chronic respiratory diseases including noncystic fibrosis (non-CF) bronchiectasis in adults. The aim of this study was to investigate the frequency of MBL2 gene polymorphisms in children with non-CF bronchiectasis, and the effect of MBL deficiency on disease severity. METHODS: Fifty children with non-CF bronchiectasis (bronchiectasis group) and 50 healthy controls (control group) were included. The demographic findings, number of acute pulmonary exacerbations in the previous year, airway cultures, pulmonary function tests, and radiologic scores of the bronchiectasis group were recorded. DNA extraction was performed in both groups and MBL2 gene polymorphisms in codons 52, 54, 57 in exon 1 and H/L, Y/X in the promoter region were studied using real-time polymerase chain reaction. Haplotypes were made by genotypes, and MBL serum expression was classified according to the genotypes in the literature. RESULTS: The bronchiectasis group consisted of 23 (46%) patients with primary ciliary dyskinesia, 5 (10%) with primary immunodeficiency diseases, and 22 (44%) with idiopathic bronchiectasis. There were no statistically significant differences between the bronchiectasis and control groups in terms of allele and genotype frequencies of polymorphisms in codons 52, 54, 57 in exon 1 and promoter H/L. However, the YX heterozygote genotype was more frequent in the control group (82%) compared with the bronchiectasis group (50%) (P = .002). The frequency of patients with intermediate serum MBL expression genotype was higher in the bronchiectasis group (20%) than in the control group (0%) (P = .001). In the bronchiectasis group, there were no significant differences in growth, annual pulmonary exacerbation rates in the last year, pulmonary function tests, radiologic scores, and microbiologic findings between low, intermediate, and high-expressing genotypes. CONCLUSIONS: In children with non-CF bronchiectasis, MBL genotype was different from healthy controls. MBL deficiency associated only with MBL genotype was not related to disease severity in this group of patients.

Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome.

Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy-Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell-cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

Congenital Mirror Movements in Gorlin Syndrome: A Case Report With DTI and Functional MRI Features.

Congenital mirror movements are rare conditions that define the inability to perform unimanual movements. Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a genetic disorder with multiple nevi predisposing to basal cell carcinoma, odontogenic keratocysts, and skeletal malformations. Herein we report on an adolescent patient with Gorlin syndrome and coexisting congenital mirror movements. To our knowledge, this is the first patient in the literature who has both of these very rare conditions.

Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis.

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center. MATERIALS AND METHODS: The study included eight patients with MOPD II that were analyzed via molecular testing, and physical and laboratory examinations. RESULTS: Molecular testing showed that seven of the eight patients had pericentrin (PCNT) gene mutations. Hematological evaluation showed that 7 (87.5%) patients had thrombocytosis, 6 (75%) had leukocytosis, 5 (62.5%) had both leukocytosis and thrombocytosis, and 2 (25%) had anemia. CONCLUSIONS: We report leukocytosis and thrombocytosis as a common hematologic abnormality in patients with MOPD II. The present findings may improve our understanding of the potential function of the PCNT gene in hematopoietic cell proliferation and differentiation.

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia.

Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syndrome involving the cranium, face, and thorax. The characteristic features are cranial involvement with macrocrania at birth, brachycephaly, various CT/MRI findings including hypoplasia of corpus callosum, enlargement of septum pellicidum, and diffuse hypodensity of the grey matter, flat face, hypertelorism, cleft lip and cleft palate, low-set, posteriorly rotated ears, short neck, and multiple costal and vertebral anomalies. The underlying genetic defect remains unknown. Using combination of homozygosity mapping and whole-exome sequencing, we identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in the human transmembrane and coiled-coil domains protein 1 (TMCO1) in four out of five families of Turkish origin. The entire critical region on chromosome 1q24 containing TMCO1 was excluded in the fifth family with characteristic findings of CFT providing evidence for genetic heterogeneity of CFT spectrum. Another founder TMCO1 mutation has recently been reported to cause a unique genetic condition, TMCO1-defect syndrome (OMIM #614132). TMCO1-defect syndrome shares many features with CFT. This study supports the fact that "TMCO1-defect syndrome," initially thought to represent a distinct disorder, indeed belongs to the genetically heterogeneous CFT dysplasia spectrum.

Medical management of moyamoya disease and recurrent stroke in an infant with Majewski osteodysplastic primordial dwarfism type II (MOPD II).

UNLABELLED: We report an infant diagnosed with Majewski osteodysplastic primordial dwarfism type II at age 8 months, who experienced cerebrovascular morbidities related to this entity. Molecular analysis identified c.2609+1 G>A, intron 14, homozygous splice site mutation in the pericentrin gene. At age 18 months, she developed recurrent strokes and hemiparesis. Brain magnetic resonance imaging and magnetic resonance angiography showed abnormal gyral pattern, cortical acute infarcts, bilateral stenosis of the internal carotid arteries and reduced flow on the cerebral arteries, consistent with moyamoya disease. In Majewski osteodysplastic primordial dwarfism type II, life expectancy is reduced because of high risk of stroke secondary to cerebral vascular anomalies (aneurysms, moyamoya disease). Periodic screening for vascular events is recommended in individuals with Majewski osteodysplastic primordial dwarfism type II every 12-18 months following diagnosis. Our patient was medically managed with low molecular weight heparin followed with aspirin prophylaxis, in addition to carbamazepine and physical rehabilitation. CONCLUSION: We report an infant with moyamoya disease and recurrent stroke presenting 10 months after diagnosis (at age 18 months), and discuss the outcome of nonsurgical medical management. The presented case is the second youngest case developing stroke and moyamoya disease.

WAGR syndrome with tetralogy of Fallot and hydrocephalus.

Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome occurs sporadically due to deletion of chromosome 11p13. A variety of other abnormalities involving different systems have been reported in patients with WAGR syndrome. We report on a patient with WAGR syndrome with accompanying tetralogy of Fallot and hydrocephalus.

TAP1 and TAP2 gene polymorphisms in childhood cystic echinococcosis.

The incidence of cystic echinococcosis (CE) due to Echinococcus granulosus is as high as 2000-2500 patients per year in Turkey. Whether genetic characteristics of the Turkish population cause a tendency to the disease is currently unknown. We aimed at studying the role of TAP gene polymorphisms in Turkish children with cystic echinococcosis. For an overview of allelic distribution of TAP1 and TAP2 genes, genotypes of 85 patients with CE and 100 controls were studied. To determine the genotype-phenotype correlation, 81 of the patients whose clinical data were available were analyzed. For TAP1-637, Asp/Gly heterozygosity was significantly more prevalent in CE patients than in controls (20 vs. 4%, odds ratio 6.0), while Gly/Gly homozygosity was less frequent (5 vs. 14%). For TAP2-379, Ile/Val heterozygosity was significantly more prevalent in CE patients than in controls (14 vs. 1%, odds ratio 16.27), while Ile/Ile homozygosity was less frequent (13 vs. 25%). TAP1-637 and TAP2-379 polymorphisms may have a role in causing genetic tendency for CE in children. The data may reflect the genetic properties of the Turkish population or may reveal the minor role of TAP gene polymorphisms in CE.

Prenatally diagnosed lethal type Larsen-like syndrome associated with bifid tongue.

Larsen syndrome is characterized by multiple joint dislocations, associated with a typical facial appearance and frequently other abnormalities. Both dominant and recessive patterns of inheritance have been reported. A lethal form of Larsen syndrome (Larsen-like syndrome) has been described as a combination of the Larsen phenotype and pulmonary hypoplasia. In this report, we present a 24-week-old female fetus with a possible prenatal diagnosis of thanatophoric dysplasia in whom postmortem examination revealed lethal type Larsen-like syndrome associated with bifid tongue, severe micrognathia and non-immune hydrops fetalis. These findings have not been reported previously in the lethal type Larsen syndrome.

Childhood intrathoracic Hodgkin lymphoma with hypertrophic pulmonary osteoarthropathy: a case report and review of the literature.

UNLABELLED: Hypertrophic osteoarthropathy (HOA) is characterized by clubbing, periosteal new bone formation and polyarthritis. The pathogenesis of clubbing involves an increased expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) from the digitally lodged platelet clumps, which bypass the pulmonary capillary network as a result of various systemic disorders. Intrathoracic neoplasms are rare causes of HOA in children. We report here a 14-year-old boy with digital clubbing, who eventually received the diagnosis of intrathoracic Hodgkin lymphoma (HL) and HOA. Eight cases previously reported with these two diagnoses are reviewed to emphasize the prognostic significance of HOA in childhood HL. CONCLUSION: Given the pathogenesis of clubbing and the prognostic significance of HOA, intrathoracic disease should be considered when HOA is detected in a child with a known or suspected malignant disease, and the occurrence of HOA during follow-up should alert the physicians for possible recurrence of the neoplastic disease or intrathoracic involvement.

Cerebro-facio-thoracic dysplasia: expanding the phenotype.

We report a further two patients with cerebro-facio-thoracic dysplasia, a rare autosomal recessive condition with thoracic costovertebral dysplasia, developmental delay and characteristic facial features. One of our patients has the additional features of large, bilateral colobomas of the optic nerve, ptosis, small conical teeth and severe left-sided talipes. He also has hypermobile joints, especially in his hands and anterior subluxation of the shoulders. The second patient has hypodensity of the grey matter on magnetic resonance imaging, which is the second report of this finding in cerebro-facio-thoracic dysplasia. In addition, he has hypoplasia of the corpus callosum. These cases illustrate the expanding phenotype of this condition, and support the hypothesis that this is an autosomal recessive condition.

Is Dandy-Walker malformation associated with "distal 13q deletion syndrome"? Findings in a fetus supporting previous observations.

We report on a fetus with a large deletion of the distal part of the long arm of chromosome 13, (del(13)(q14 --> qter)) congenital anomalies of the urinary system, lungs and extremities, and Dandy-Walker malformation (DWM). Although DWM has been associated with many chromosomal abnormalities and genetic syndromes, its relation to the distal 13q has been demonstrated recently. In 2002, McCormack et al., described two patients with deletions of the long arm of chromosome 13 who had multiple congenital abnormalities along with holoprosencephaly (HPE) and DWM. The phenotypic features and autopsy findings of a fetus with "distal 13q deletion syndrome" at 22 weeks gestation are discussed and comparison with the previous two cases is made. The findings support the previous hypothesis suggesting that haploinsufficiency at a locus within 13q22-33 due to microdeletions may be responsible for isolated DWM in some of the patients. Detailed examination of 13q (13q22-33) by means of conventional and molecular cytogenetic methods is necessary in cases with DWM.