Further Expanding the Mutational Spectrum of Gorlin Syndrome in Three Unrelated Families.

Introduction: Gorlin syndrome is a rare, autosomal dominant multi-systemic disorder with a predisposition to the development of cancers such as medulloblastoma and nevoid basal cell carcinoma. Heterozygous pathogenic variants in PTCH1 are responsible for 90% of Gorlin syndrome cases. Pathogenic variants in PTCH1 cause overstimulation of the sonic hedgehog signaling pathway, which plays a role in the development of embryonic structures and tumorigenesis. Clinical major and minor diagnostic criteria for Gorlin syndrome have been determined. Odontogenic keratocyst (OKC) is the most common reason for medical admission in Gorlin syndrome. In this article, it is aimed to draw attention to the fact that patients with Gorlin syndrome are not very rare in our country and the variability in phenotypic and dysmorphic findings may be a clue for the diagnosis. Methods: Exome sequencing was performed on the Illumina NextSeq550 System platform by using the Ion Ampliseq exome RDY kit for Illumina. Sanger sequencing was performed accordingly for the other affected individuals in both families. Results: In this study, the clinical and molecular findings of 9 Gorlin syndrome patients from three unrelated families are presented. Macrocephaly, calcification of falx cerebri, palmar-plantar pits, rib anomalies, and OKC were detected in decreasing order in more than half of the patients. A novel heterozygous frameshift PTCH1 variant in family 1, a nonsense previously reported PTCH1 variant in family 2, and a novel heterozygous splice-site PTCH1 variant in family 3 were detected. Conclusion: Gorlin syndrome should be kept in mind in patients presenting with macrocephaly, palmoplantar pits, and OKC history. Careful examination of all family members is essential in the timely diagnosis of other affected individuals with minor phenotypic findings.

Review of patients with achondroplasia: a single-center's experience with follow-up and associated morbidities.

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.

Hyaline fibromatosis syndrome: a rare, yet recognizable syndrome.

BACKGROUND: Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey. METHODS: Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser. RESULTS: Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years. CONCLUSIONS: HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.

A novel GRK2 variant in a patient with Jeune asphyxiating thoracic dysplasia accompanied by Morgagni hernia.

Skeletal ciliopathies constitute a subgroup of ciliopathies characterized by various skeletal anomalies arising from mutations in genes impacting cilia, ciliogenesis, intraflagellar transport process, or various signaling pathways. Short-rib thoracic dysplasias, previously known as Jeune asphyxiating thoracic dysplasia (ATD), stand out as the most prevalent and prototypical form of skeletal ciliopathies, often associated with semilethality. Recently, pathogenic variants in GRK2, a subfamily of mammalian G protein-coupled receptor kinases, have been identified as one of the underlying causes of Jeune ATD. In this study, we report a new patient with Jeune ATD, in whom exome sequencing revealed a novel homozygous GRK2 variant, and we review the clinical features and radiographic findings. In addition, our findings introduce Morgagni hernia and an organoaxial-type rotation anomaly of the stomach and midgut malrotation for the first time in the context of this recently characterized GRK2-related skeletal ciliopathy.

A rare skeletal dysplasia in the etiology of severe scoliosis: Diaphanospondylodysostosis.

Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the BMPER gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel BMPER mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature.

ADPRHL2 is involved in posttranslational modification and is known to have a role in physiological functions such as cell signaling, DNA repair, gene control, cell death, and response to stress. Recently, a group of neurological disorders due to ADPRHL2 variants is described, characterized by childhood-onset, stress-induced variable movement disorders, neuropathy, seizures, and neurodegenerative course. We present the diagnostic pathway of two pediatric patients with episodic dystonia and ataxia, who later had a neurodegenerative course complicated by central hypoventilation syndrome due to the same homozygous ADPRHL2 variant. We conducted a systematic literature search and data extraction procedure following the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 statement in terms of patients with ADPRHL2 variants, from 2018 up to 3 February, 2023. In total, 12 articles describing 47 patients were included in the final analysis. Median age at symptom onset was 2 (0.7-25) years, with the most common presenting symptoms being gait problems (n = 19, 40.4%), seizures (n = 16, 34%), ataxia (n = 13, 27.6%), and weakness (n = 10, 21.2%). Triggering factors (28/47; 59.5%) and regression (28/43; 60.4%), axonal polyneuropathy (9/23; 39.1%), and cerebral and cerebellar atrophy with white matter changes (28/36; 77.7%) were the other clues. The fatality rate and median age of death were 44.6% (n = 21) and 7 (2-34) years, respectively. ADPRHL2 variants should be considered in the context of episodic, stress-induced pediatric and adult-onset movement disorders and seizures.

Coexistence of Two Rare Conditions Complicating the Other's Management: Propionic Acidemia and Apert Syndrome.

Introduction: Propionic acidemia (PA) is an inborn error of organic acid metabolism inherited in an autosomal recessive manner. The neonatal-onset disease may present with feeding difficulties and vomiting; seizures, coma, and death may occur if untreated. In addition, catabolic processes such as infections and surgical procedures could cause metabolic decompensation, so patients with organic acidemia should be followed closely. Case Presentation: Here, a patient diagnosed with PA and Apert syndrome in the neonatal period and the complications caused by the coexistence of the two entities are mentioned. The difficulties precipitated by the coexistence of Apert syndrome and PA make this case unique. She has had prolonged hospitalizations due to metabolic decompensations after cranioplasty and inguinal hernia repair, both triggered by nosocomial respiratory infections, complicating both the surgical treatment of Apert syndrome and the management of PA. Conclusion: Coexistence of these two serious disorders mandates a more prudent clinical management as Apert syndrome patients undergo several surgical procedures, rendering them susceptible to catabolic decompensations.

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families.

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome (LMS), Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT), Rapp-Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

CHRND variant in a paternally inherited esophageal atresia and tracheoesophgageal fistula: Report of a case.

BACKGROUND: The familial occurrence of esophageal atresia and tracheoesophageal fistula (EA-TEF) is very rare and the genetic basis behind the isolated familial cases have not been identified. A male infant born with EA-TEF and his affected father were evaluated with whole genome sequence to define a genetic causative variation in paternally inherited EA-TEF. CASE REPORT: A male infant was born to 29-years-old, gravida 1, para 1 women by normal vaginal delivery. The patient was diagnosed as Type-C EA-TEF. In his family history, his father was also operated for EA-TEF during neonatal period. He had no associated anomaly despite patent foramen ovale. Genomic DNAs were extracted from peripheral blood of the patient and the father. When causative genes responsible for EA-TEF were filtered out, four different variants in NOTCH2, SAMD9, SUPT20H and CHRND were found. Except the variant found in CHRND (NM_000751.2, c.381C>G, p.(Tyr127Ter)), other three variants were not found to be segregated with the father who has EA-TEF also. This nonsense variant was not found in GnomAD database. CONCLUSION: CHRND variant found in both EA-TEF patient and his affected father suggest that CHRND variant might possibly be considered as one of the causative genetic variants in familial isolated EA-TEF patients.

Mutated Transcripts of ZEB2 Do Not Undergo Nonsense-Mediated Decay in Mowat-Wilson Syndrome.

Introduction: Mowat-Wilson syndrome (MWS) is an autosomal-dominant complex developmental disorder characterized by distinctive facial appearance, intellectual disability, epilepsy, and various clinically heterogeneous abnormalities reminiscent of neurocristopathies. MWS is caused by haploinsufficiency of ZEB2 due to heterozygous point mutations and copy number variations. Case Presentation: We report on two unrelated affected individuals with novel ZEB2indel mutations, molecularly confirming the diagnosis of MWS. Quantitative real-time polymerase chain reaction (PCR) for the comparison of total transcript levels and allele-specific quantitative real-time PCR were also performed and demonstrated that the truncating mutations did not lead to nonsense-mediated decay as expected. Conclusion: ZEB2 encodes a multifunctional pleiotropic protein. Novel mutations in ZEB2 should be reported in order that genotype-phenotype correlations might be established in this clinically heterogeneous syndrome. Further cDNA and protein studies may help elucidate the underlying pathogenetic mechanisms of MWS since nonsense-mediated RNA decay was found to be absent in only a few studies including this study.

Evaluation of polysomnography findings in children with genetic skeletal disorders.

Children with genetic skeletal disorders have variable conditions that can lead to sleep-disordered breathing, and polysomnography is the gold standard for diagnosing this condition. We aimed to review polysomnography findings, to assess the severity of sleep apnea, and to investigate the clinical variables predictive of sleep-disordered breathing in these patients. We retrospectively collected the medical records of patients with genetic skeletal disorders who underwent polysomnography for 5 years. Twenty-seven children with various genetic skeletal disorders, including achondroplasia (14), Crouzon syndrome (3), acromesomelic dysplasia Maroteaux type (3), Apert syndrome (2), osteopetrosis (1), Jeune dysplasia (1), Desbuquois dysplasia (1), acrodysostosis (1), and spondyloepiphyseal dysplasia (1) were enrolled. The median age at the first polysomnography was 58 (1st-3rd quartile: 31-113) months. The overall sleep-disordered breathing results were: 19 (70.3%) had obstructive sleep apneas (OSA) (4 mild, 6 moderate, 9 severe), 2 (7.4%) had central apneas, 4 (14.8%) had nocturnal hypoventilation. There was a significant correlation between non-ambulatory status with both total AHI and OSA (p < 0.001, rho: -0.66/p = 0.04, rho: 0.38, respectively). Nine patients received positive airway pressure titration, and the oAHI values of all returned to the normal range. These patients were started with positive airway pressure treatment. Our cohort showed that the majority of the patients with skeletal dysplasia had sleep apnea syndrome characterised mainly by OSA, highlighting the importance of polysomnography screening for sleep disorders. Positive airway pressure therapy represents an effective treatment for sleep-disordered breathing in those patients.

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Assessing the Menstrual Cycle and Related Problems in Adolescents with a Genetic Syndrome Associated with Intellectual Disability.

STUDY OBJECTIVE: The aim of this study was to assess the experience and quality of life (QoL) related to menstruation in adolescents with a genetic syndrome accompanying intellectual disability (ID). METHODS: This prospective cross-sectional study was conducted on 49 adolescents with a genetic syndrome accompanied by ID, which was defined by the Wechsler Intelligence Scale for Children-Revised, and 50 unaffected controls. In a survey created by the authors, demographic information, menstrual history, and information regarding menstrual difficulties, school abstinence, dysmenorrhea, and premenstrual changes were collected. The Childhood Health Assessment Questionnaire was used to evaluate physical impairment, whereas the QoL scale was utilized to evaluate QoL in general and during menstruation. Data were collected from caregivers and additionally from the participants with mild ID, whereas in the control group, data were collected from the participants. RESULTS: Menstrual history was similar between the 2 groups. Menstruation-related school absenteeism was higher among the ID group (8% vs 40.5%, P < .001). Mothers reported that 73% of their daughters needed help with menstruation care. Social, school, psychosocial functioning, and total QoL scores during menstruation were significantly lower in the ID group when compared with the controls. A significant decrease in physical, emotional, social, psychosocial functioning, and total QoL score occurred during menstruation in the ID group. None of the mothers requested menstrual suppression. CONCLUSION: Although menstrual patterns in the 2 groups were similar, QoL decreased significantly while menstruating in the ID group. Despite a decrease in QoL, an increase in school absenteeism, and a high percentage of needing assistance while menstruating, none of the mothers requested menstrual suppression.

A novel biallelic CRIPT variant in a patient with short stature, microcephaly, and distinctive facial features.

Primordial dwarfism (PD) is one of a highly heterogeneous group of disorders characterized by severe prenatal/postnatal growth restriction. Defects in various pathways such as DNA repair mechanism, impaired centrioles, abnormal IGF expression, and spliceosomal machinery may cause PD including Seckel syndrome, Silver-Russell syndrome. Microcephalic osteodysplastic primordial dwarfism (MOPD) types I/III, II, and Meier-Gorlin syndrome. In recent years with the wide application of exome sequencing (ES) in the field of PD, new genes involved in novel pathways causing new phenotypes have been identified. Pathogenic variants in CRIPT (MIM# 604594) encoding cysteine-rich PDZ domain-binding protein have recently been described in patients with PD with a unique phenotype. This phenotype is characterized by prenatal/postnatal growth restriction, facial dysmorphism, ocular abnormalities, and ectodermal findings such as skin lesions with hyper/hypopigmented patchy areas and hair abnormalities. To our knowledge, only three patients with homozygous or compound heterozygous variants in CRIPT have been reported so far. Here, we report on a male patient who presented with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant c.7_8delTG; p.(Cys3Argfs*4) was detected in CRIPT with the aid of ES. With this report, we further expand the mutational and clinical spectrum of this rare entity.

A lethal and rare cause of arthrogryposis: Glyt1 encephalopathy.

Glycine encephalopathy with normal serum glycine (MIM #617301), also known as GLYT1 encephalopathy, is an extremely rare disorder caused by biallelic variants in SLC6A9 and characterised by facial dysmorphic features, skeletal findings including contractures, knee hyperextension, and joint dislocations and seizures. To date, only ten patients from five families have been reported and only two of them could survive until childhood. In this study, we report on a consanguineous Turkish couple with a history of six pregnancies with three habitual abortions and three postpartum exitus. While in three pregnancies the babies were born prematurely at 32nd gestational week by emergency ceserean section due to hydrops and fetal distress, the other pregnancy was medically terminated at 16th gestational week due to absent fetal heart activity. The product of all these three pregnancies exhibited similar phenotype including short neck, thoracic kyphosis, hypertrichosis, joint contractures and dislocations, hypertonia, knee hyperextension and facial dysmorphic features. Trio exome sequencing was performed prenatally during the last pregnancy and a novel VUS variant in SLC6A9 and a likely pathogenic variant in MTOR gene were detected. DNA isolation was performed from frozen muscle and adrenal tissue of previously autopsied fetuses with similar clinical features, and the same variants were confirmed in both of them. Our data suggest that SLC6A9 and MTOR variants may be responsible for this extremely lethal phenotype in this family.

Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3.

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.

Diagnostic distribution and postnatal evaluation of prenatally detected short femur: A single center experience.

Genetic skeletal disorders (GSDs) are clinically and etiologically heterogeneous group of disorders caused by abnormal growth and development of bone and/or cartilaginous tissues. Timely and accurate diagnosis is essential for prevention of significant comorbidities. In this study demographic, parental, prenatal and natal characteristics, and postnatal diagnostic distribution along with follow-up processes of 104 individuals with the finding of "short femur" detected in routine prenatal ultrasonography were evaluated. Of 104 patients, 19 (18.2%) were medically terminated, 12 (11.6%) were deceased during follow-up and 73 (70.2%) were still under follow-up. Diagnostic distribution of 104 patients was as follows: 77 (74%) had GSD, eight (7.7%) had chromosomal disorder, seven (6.7%) were completely normal, and 12 (11.5%) had no definite diagnosis. Long-term follow up evaluation contributed to clinical diagnosis in four patients. When grouped according to Nosology and Classification of GSDs: 2019 revision, the most frequent (n = 30, 38.5%) group was "FGFR3 chondrodysplasia group", followed by "Type 2 collagen group" (n = 7, 9%), and "Osteogenesis imperfecta and decreased bone density group" (n = 5, 6.4%). The finding of prenatally detected "short femur" represents a group of diverse diagnosis with heterogeneous etiology. GSDs are the most common etiology among fetuses with short extremity.