Dysmorphic Research Articles

Child with hypocalcaemia: a rare case of HDR syndrome

Barakat syndrome (also known as HDR syndrome) is an autosomal dominant disorder characterized by the triad of Hypoparathyroidism (H), nerve Deafness (D) and/or renal disease caused by mutation of the GATA3 gene located at chromosome 10p15. This syndrome is very rare with exact prevalence not known and only few cases are reported in the literature. 4-month-old baby girl, diagnosed as hypoparathyroidism on supplements, presented with seizures due to hypocalcemia. On detailed evaluation, child was found to have bilateral hearing loss. Facial dysmorphisms were noted in the form of bulbous nose with everted nares, long philtrum, thin upper lip, low set ears and bilateral non paralytic convergent squint. External genitalia showed perianal groove with an anteriorly placed anus. Startle response was blunted. Other systemic examination was within normal limits. Routine blood investigations revealed low serum calcium (calcium (total) 4.8 mg/dl) and high serum phosphorous level (11.3 mg/dl). Serum parathormone level was 4.4pg/ml and vitamin D levels were insufficient. Child was managed with IV calcium correction and 1,25 (OH)2 VIT D3. The brainstem evoked response audiometry (BERA) showed severe hearing loss. Next - generation sequencing showed a heterozygous missense variant in exon 4 of the GATA 3 gene which was suggestive of Hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome. This case report aims to provide awareness of rare inherited conditions in a patient with abnormal physical and laboratory findings even though their initial presentation was seizure and hypocalcemia.

Thick skin and thicker arteries: case report on a rare cause of hypertension.

Renovascular hypertension is the second leading cause of hypertension. Twenty-seven genes have been attributed to monogenic renovascular hypertension at present. We present a 15-year-old boy with facial dysmorphism, thick skin and renovascular hypertension with a novel gain-of-function variant in SMAD4 gene suggesting Myhre syndrome. Hypertension was controlled with three anti-hypertensive agents and vascular intervention is planned. It is characterized by a multisystem connective tissue disorder associated with progressive fibrosis of skin, cardiovascular, musculoskeletal, gastrointestinal and respiratory systems. This case highlights the need for recognizing syndromic features in children with renovascular hypertension.

Maternally Derived Complex Small Supernumerary Marker Chromosome 22 Associated with Cat-Eye Syndrome Like Features

Cat-eye syndrome (CES) is a rare genetic disease first reported in 1965. The estimated prevalence of CES is 1:50,000 to 1:150,000, and it is typically associated with an inverted duplicated small supernumerary marker chromosome (sSMC) derived from chromosome 22. The specific chromosomal band involved in CES causing partial tetrasomy is 22q11.21, where chromosomal rearrangements occur due to the presence of low-copy repeats (LCR22). The phenotype of CES is extremely diverse, ranging from normal to multiple abnormalities including intellectual disabilities and dysmorphic features. To our knowledge, over 340 patients with CES have been reported to date. This study reports a patient displaying a duplication of chromosome 22pter-22q12 involving band 22q11.21 where the CES critical region is located, and 18pter to 18p11. The propositus is a three-year-old girl, born to an unrelated and healthy couple. She was referred for facial dysmorphism and psychomotor delay. Banding cytogenetic analysis revealed an sSMC resulting from abnormal 3:1 segregation of the maternal balanced translocation t(18;22). Furthermore, the origin of the sSMC was confirmed by fluorescence in situ hybridization technique. The current study emphasized the importance of molecular cytogenetic techniques such as FISH in apprehending chromosomal abnormality. In addition, it shows that partial trisomy 22q11.2 to 22q12 may lead to CES-like symptoms.

Systematic Review: Fragile X Syndrome Across the Lifespan with a Focus on Genetics, Neurodevelopmental, Behavioral and Psychiatric Associations

Background/Objectives: Fragile X syndrome (FXS) is one of the most common genetic causes of intellectual developmental disability and autism spectrum disorder (ASD), second only to Down’s syndrome and associated with a broad range of neurodevelopmental, behavioral, and psychiatric challenges. FXS may be present in infants or young children with characteristic dysmorphic features, developmental delays, and behavioral challenges. The diagnosis of FXS is confirmed by the molecular genetic testing of the FMR1 gene encoding fragile X messenger RNA-binding protein (FMRP), involved in regulating the translation of multiple mRNAs which play a key role in neuronal development and synaptic plasticity. Understanding the genetic cause, pathophysiology, and natural history of FXS is crucial for identifying commonly associated comorbidities, instituting effective therapeutic interventions, and improving long-term outcomes. Methods: This systematic review employed a comprehensive literature search using multiple electronic databases including PubMed, Web of Science, and Scopus with keywords related to fragile X syndrome, lifespan, genetics, neurodevelopmental, behavioral, and psychiatric disorders. Results: FXS is associated with an increased risk for specific neurodevelopmental, or psychiatric disorders. Symptoms and challenges associated with FXS vary based on multiple factors, including genetic differences, age, sex, comorbid conditions, various environmental influences, the availability of support, and opportunities for therapeutic interventions. Knowledge of these associations helps guide caregivers and clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families. Conclusions: The focus of this article is to explore and describe the genetic underpinnings of FXS, identify associated developmental, behavioral, and psychiatric conditions over the lifespan, and provide a review of clinical features, therapeutic interventions including investigational treatments, and current research updates.

Normative Values of Rhinology Questionnaires in Young Adults: A Tool to Identify Candidates for Rhinoplasty

Objective: Normative values of Rhinoplasty Outcome Evaluation (ROE) and Functional Rhinoplasty Outcome Inventory 17 (FROI-17) allow the monitoring of surgery outcomes. The objective of our study was to determine the reference norms of these disease-specific questionnaires in the age group that most often seeks rhinoplasty. Methods: The normative values of the ROE and FROI-17 questionnaires were calculated for 570 (459 women and 111 men) young adults at the mean age of 19.3 ± 1.3 years, range 18–25 years. Each participant underwent an ENT examination. All those who obtained a positive result were asked to complete two questionnaires: ROE and FROI-17. Results: The mean total ROE score was 13.4 ± 2.3, with a median of 13 and a range from 7 to 24. The mean overall FROI-17 score was 9.1 ± 13.3, with a median of 4 and a range from 4 to 72. For nasal symptoms, the mean was 4.0 ± 6.0, with a median of 1 and a range from 0 to 29. We observed a statistically significant difference between men and women only for the normative values of nasal symptoms (mean 4.0 ± 5.9 and median 2 (0–27) vs. mean 3.7 ± 6.5 and median 0 (0–29)). Additionally, there was a statistically significant correlation between the normative values of the ROE and FROI-17 scores (ρs = −0.413 for all participants, ρs = −0.314 for women, and ρs = −0.437 for men). Conclusions: The established normative values for the ROE and FROI-17 questionnaires among young, healthy individuals without nasal abnormalities can assist in the initial assessment of individuals seeking rhinoplasty. Deviations from these normative values in the ROE and FROI-17 questionnaires results may serve as indicators of potential concerns, such as body dysmorphic disorder (BDD).

Association Between Symptoms of Body Dysmorphia and Social Media Usage: A Cross-Generational Comparison.

Background: The rise of social media parallels a mental health epidemic. The effect of social media usage on rates and severity of body dysmorphic disorder is not well-understood. Objective: To determine if an association exists between social media engagement, body dysmorphia symptoms, and/or interest in cosmetic surgery in a demographically diverse cross-section of the U.S. adult population. Methods: In a Qualtrics platform-based survey study of the general U.S. adult population, responses to demographic information, social media activity questionnaire and the body dysmorphic disorder screening questionnaire, and interest in cosmetic surgery were collected. Descriptive statistics and a multivariate logistic regression model were carried out. Results: A total of 1,013 respondents completed the survey. The average age was 40.9 (SD, 14.8) years, 72% were women. Median time spent on social media (IQR) was 4 (2-7) h/day. Respondents who screened positive for symptoms of body dysmorphia had higher daily mean social media usage time (odds ratio [OR] 1.49), tend to be female (OR 2.17), younger (OR 0.97), identify as Caucasian (OR 1.65), and are more likely considering a cosmetic procedure in the next year (OR 2.98). Conclusion: This study demonstrates a positive association between daily social media usage, self-reported symptoms of body dysmorphia, and interest in cosmetic procedures.

Case Report: The first Korean familial case of BCAP31-related deafness, dystonia, and cerebral hypomyelination

Deafness, dystonia, and central hypomyelination (DDCH) syndrome (OMIM #300475) is a rare X-linked genetic disorder characterized by developmental delays, deafness, central hypomyelination, and dystonia. We report the first Korean familial case involving twin boy and girl carrying a novel pathogenic BCAP31 variant which was inherited from their mother. The male proband, born prematurely with very low birth weight (VLBW), exhibited severe global developmental delay, microcephaly, failure to thrive, dystonia, seizures, sensorineural hearing loss (SNHL) requiring cochlear implantation, and mild facial dysmorphism. A brain MRI revealed white matter atrophy, thinning of the corpus callosum, and delayed myelination. The twin sister presented with mild developmental delays and bilateral SNHL but did not experience seizures or dystonia. Their mother also had bilateral SNHL. Whole genome sequencing identified a hemizygous pathogenic variant, c.247C>T (p.Gln83Ter), in the BCAP31 in the proband. The variant was also found in his mother and twin sister, who exhibited less severe symptoms. Early genetic evaluation via next-generation sequencing is crucial for timely diagnosis and intervention, particularly in VLBW infants with genetic disorders. This report expands the understanding of genotype-phenotype correlations in DDCH syndrome and highlights the variable phenotypes in manifesting females.

Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay.

The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities. Here, we provide genetic and phenotypic information for two individuals harboring de novo variants at p.Arg225 and sharing a highly similar phenotype. This report suggests a relationship between variants at this amino acid position and autosomal dominant disease, and further studies will be needed to characterize this disease-gene relationship and elucidate the disease mechanism.

Fetal Alcohol Syndrome: Impact on Neurodevelopment, Diagnosis, Early Intervention and Motor Disorders in Children under 3 Years

Fetal Alcohol Syndrome (FAS) is the most severe outcome of prenatal alcohol exposure, characterized by a combination of somatic and neurological abnormalities, including facial dysmorphism, growth deficits, and neurocognitive impairments. Fetal Alcohol Spectrum Disorders (FASD) encompass a broader range of outcomes from prenatal alcohol exposure, with varying degrees of severity. Alcohol consumption during pregnancy can disrupt fetal development, with no known safe threshold for its intake at any stage of gestation. The consequences are particularly profound on the central nervous system (CNS), where damage to structures like the cerebellum can lead to motor dysfunctions, balance issues, and cognitive impairments. Early identification and diagnosis of FAS or FASD, especially during the critical first years of life, is essential for improving developmental outcomes. Intervention strategies, including physical and cognitive therapy, can help mitigate long-term disabilities associated with these conditions. Diagnostic methods, such as ultrasound for fetal structural abnormalities and the AUDIT screening tool, are integral for early detection. This review highlights the impact of prenatal alcohol exposure on motor skill development, particularly the persistence of primitive reflexes in infants with FAS, which is indicative of CNS immaturity and necessitates early therapeutic interventions. Understanding these motor and neurological markers is critical for providing appropriate support and improving outcomes for affected children.

Witteveen-Kolk Syndrome With Cleft Palate: A Case Report and Review of the Literature.

Witteveen-Kolk syndrome (WITKOS) is an exceptionally uncommon genetic and neurodevelopmental disorder, characterized by developmental delay, mild intellectual disability, and craniofacial dysmorphic features. Although cleft palate (CP) has rarely been reported in WITKOS, CP in this condition has not been assessed in detail. Here, we present a case of WITKOS with a CP. The patient was a 2-year-old male and he was referred to our clinic with CP and dysmorphic clinical findings. Screening for CP should be considered when a diagnosis of WITKOS is made. CP repair can be performed successfully after neurodevelopmental maturation is complete.

NUBP2 deficiency disrupts the centrosome-check point in the brain and causes primary microcephaly.

Microcephaly affects 1 in 2,500 babies per year. Primary microcephaly results from aberrant neurogenesis leading to a small brain at birth. This is due to altered patterns of proliferation and/or early differentiation of neurons. Premature differentiation of neurons is associated with defects in the centrosome and/or primary cilia. In this study, we report on the first patients identified with NUBP2 -deficiency and utilize a conditional mouse model to ascertain the molecular mechanisms associated with NUBP2 -deficient primary microcephaly. We identified homozygous NUBP2 variants in these patients who displayed profound primary microcephaly in addition to intrauterine growth restriction, cervical kyphosis, severe contractures of joints, and facial dysmorphia. We then generated a mouse model using Emx1-Cre to ablate Nubp2 from the forebrain. The mice presented with severe microcephaly starting at E18.5. Neurospheres generated from the forebrain of Emx1-Cre; Nubp2 flox/flox conditional deletion mice were used to support the pathogenicity of the patient variants. We show that loss of Nubp2 increases both canonical and non-canonical cell death, but that loss of p53 fails to rescue microcephaly in the mouse model. Examination of neurogenesis in Emx1-Cre; Nubp2 flox/flox mice revealed distinct alterations in proliferation and cellular migration accompanied by supernumerary centrosomes and cilia. We therefore propose that NUBP2 is a novel primary microcephaly-related gene and that the role of Nubp2 in centrosome and cilia regulation is crucial for proper neurogenesis.

Impact of pubertal timing on growth progression and final height in subjects affected by RASopathies

BackgroundRASopathies, including Noonan syndrome and related disorders, are multisystem conditions caused by mutations in various genes encoding proteins involved in the RAS/MAPK signaling pathway resulting in increased signal flow. They are clinically characterized by failure to thrive, facial dysmorphisms, congenital heart defects, lymphatic malformations, skeletal anomalies, and variable cognitive impairment, with variable prevalence in the different conditions and subtypes. Pubertal development, which affects growth and final height, is often delayed in Noonan syndrome patients, though not universally. This study aimed to evaluate the timing and progression of puberty and its impact on growth and final height in patients with RASopathies.Subjects and methodsA retrospective longitudinal study was conducted involving 103 patients with molecularly confirmed RASopathies. A subgroup of 40 patients who had completed pubertal development was analyzed. Anthropometric, hormonal (FSH, LH, estradiol/testosterone), and radiological data were collected.ResultsAmong the 40 patients who had completed puberty, 75% had a diagnosis of Noonan syndrome. The median age at pubertal onset was 11.8 years in males and 13.2 years in females. Delayed puberty was observed in 27.8% of patients, with a higher incidence in females. Median final height was significantly lower in those with delayed pubertal onset compared to those with normal development (p < 0.01). No significant differences in final height were observed between patients with growth hormone deficiency treated with growth hormone and those who were untreated.ConclusionsDelayed pubertal onset negatively impacts final height in patients with RASopathies, with inadequate pubertal catch-up growth being a common outcome. While most patients initiate puberty spontaneously, careful monitoring of growth and pubertal progression is crucial to optimize therapeutic interventions and improve final height outcomes.

Development of a Preoperative Psychological Screening Tool: Piloting the Cosmetic Readiness Questionnaire (Pilot-CRQ).

Patients with psychological risk factors such as body dysmorphic disorder (BDD) and unmanaged mental health concerns are considered at higher risk for dissatisfaction with aesthetic procedures. Identifying these risks before a procedure may decrease the chance of adverse outcomes for patients and practitioners. In this study we aimed to develop a comprehensive psychological screening tool to assess patient's psychological suitability for surgical and nonsurgical aesthetic procedures. Items for the Pilot Cosmetic Readiness Questionnaire (CRQ) were developed by psychologists (n = 3) and then reviewed by plastic surgeons (n = 2) and nonsurgical cosmetic doctors (n = 3). Patient interviews (n = 15) and piloting of the questionnaire (n = 69) provided data regarding the scale's initial psychometric properties. Results supported the reliability and validity of the Pilot-CRQ's subscales of Body Dysmorphia, Psychological Distress, Self-Criticism, Perfectionism, and Lack of Openness. Lack of Openness was a validity scale that examined the degree that respondents might be underreporting symptoms. The CRQ predicted individuals with a BDD diagnosis, as rated by a blinded expert clinical psychologist, with high sensitivity and specificity. These results provide support for the Pilot-CRQ identifying people with BDD and psychological factors related to aesthetic treatment outcomes and provide a strong basis for employing the CRQ in clinical contexts and in future research.

Early Maladaptive Schemas, Body Dysmorphic Disorder (BDD) and the Mediation Role of Rumination and Emotional Cognitive Regulation: A Focus on Cosmetics Surgery Applicants

Early Maladaptive Schemas, Body Dysmorphic Disorder (BDD) and the Mediation Role of Rumination and Emotional Cognitive Regulation: A Focus on Cosmetics Surgery Applicants

The management of body dysmorphic disorder in adolescents: A systematic literature review

Abstract Body dysmorphic disorder (BDD) is a pathological body dissatisfaction characterised by delusional beliefs of a flaw in appearance paired with obsessive-compulsive rituals. This disorder has a high prevalence in adolescence. This study examines the current state of treatment for BDD in adolescents in the UK to establish a baseline of current treatment, and to identify specific areas for further research. A systematic literature review of two databases was carried out and resultant papers were organised using an amended version of the current UK management standards. Six papers met the eligibility criteria and cognitive behavioural therapy was reported as the most effective current treatment. In drawing together the key findings, three areas for further research were highlighted that are of relevance to a broad range of clinicians working in BDD management in adolescence. These included inquiry into mental health professionals’ perspectives, a review of the rate of remission rates, and research into the extent to which schools can influence adolescents’ ideas about body image. The significance of BDD is not reflected in the current literature base. Education of professionals and the wider community is warranted, as is the drive for improved awareness and an increase in the availability of treatment.

PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism.

Protein-activated kinases mediate spine morphogenesis and synaptic plasticity. PAK3 is part of the p21-activated kinases (PAKs) family of Ras-signaling serine/threonine kinases. Pathogenic variants in the X-linked gene PAK3 have been described in patients with neurodevelopmental syndromes. We analyzed an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. The male proband had drug-resistant hypermotor seizures and moderate intellectual disability. His brother had drug-responsive hypermotor seizures and mild intellectual disability. Both brothers were hemizygous and had psychiatric and behavioral problems as well as dysmorphic facial features. Their mother had never had seizures but was shown to be mosaic for the PAK3 pathogenic variant. She had normal intellect but did have short stature and dysmorphic facial features similar to her sons. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females. PLAIN LANGUAGE SUMMARY: We studied an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females.

The effect of LARP7 on gene expression during osteogenesis.

La-related protein 7 (LARP7) is a key regulator of RNA metabolism and is thought to play a role in various cellular processes. LARP7 gene autosomal recessive mutations are the cause of Alazami syndrome, which presents with skeletal abnormalities, intellectual disabilities, and facial dysmorphisms. This study aimed to determine the role of LARP7 in modulating gene expression dynamics during osteogenesis. First, the temporal expression profile of the LARP7 gene during various stages of osteogenesis was examined. Then, RNA interference-mediated knockdown of LARP7 was implemented and high-throughput RNA-seq analysis was performed in order to identify global gene expression changes associated with knockdown of LARP7. The findings show there were significant alterations in the overall gene expression profile. The observed down-regulation in extracellular matrix (ECM) component genes suggests that it might lead to impairments in the structure and function of the bone matrix. Additionally, modulation of alternative splicing events were observed, especially in the RUNX2 and SPP1, indicating the potential contribution of LARP7 to the phenotypic features observed in Alazami syndrome. Overall, the findings clarify the regulatory mechanisms of LARP7 in osteogenic differentiation and illuminate potential avenues for therapeutic interventions in patients with skeletal disorders.

Distinct Facial Dysmorphisms in a Child with Renpenning Syndrome.

Distinct Facial Dysmorphisms in a Child with Renpenning Syndrome.

The application of the facial analysis program Face2Gene in a single genetic counseling center: a retrospective study

BackgroundFace2Gene (F2G) is a software program, widely used in clinical genetics and dysmorphology for recognizing children with genetic disorders. In order to assess its accuracy in real clinical context, we applied F2G to patients from our genetic counseling center.ResultsWe randomly selected 151 children, who were referred to genetic counseling because of dysmorphic features and later diagnosed with a particular genetic condition. A frontal photograph was uploaded to the program, and at least three phenotypic traits were selected for each case. Date of birth, sex, weight, height, and head circumference were also entered in the software. The efficacy of the program to correctly diagnose the syndrome based on the facial analysis and/or phenotypic traits was assessed. In 56% (84 cases) of the patients, the F2G program accurately identified the correct diagnosis in its top three suggestions. Forty-seven percent (71 cases) of the patients had the correct diagnosis after applying only facial analysis. There was a statistically significant difference between the two types of analysis—p = 0.001. In 19 of the cases where F2G was unable to identify the correct diagnosis among the top three options based on phenotypic and facial analysis, the diagnosis was included among the 30 suggested syndromes, yielding a total success rate of 68%. The diagnosis was found in the ultra-rare syndromes’ suggestions area in six more cases.ConclusionsOur results show that F2G has a good overall performance, but adding phenotypic features to the case under study may increase even further its diagnostic capacity.

Beyond Dermatological Findings: Multisystem Involvement in Prolidase Deficiency.

Objective: Prolidase deficiency is a metabolic and immunological disorder that is inherited in an autosomal recessive manner. In prolidase deficiency, a broad spectrum of differences is observed in patients, ranging from asymptomatic to multisystem involvement. There is scarce information in the literature on the atypical features and immunophenotypes of this disease. Aim of this study is to present 4 new cases to provide information on the rare features of the disease and to raise awareness. Materials and Methods: This study included 4 female patients with prolidase deficiency. Their demographic, clinical, and immunologic characteristics were obtained from their medical records. Results: There were 4 female patients (P1-P4), with a mean age of 18.5 years (min-max: 10-29) and a mean age of symptom onset of 6.9 years (min-max: 0.04-27). The main presenting complaints of the patients were skin lesions (100%), dysmorphic features (100%), neurodevelopmental delay (100%), frequent infections (100%), and prolonged diarrhea (50%). P2 had diffuse large B-cell lymphoma, resulting in early death. Interestingly, P1 and P2 experienced opportunistic infections such as cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. Three patients (75%) had lymphopenia. Two patients had elevated IgE levels. Lymphocyte subgroup analysis showed an inverted CD4/CD8 ratio in all patients. In patients P1 and P2, the percentages of naive T cells and recent thymic emigrants were reduced, suggesting combined immune deficiency at the time of diagnosis. CD19+ B cells were also low in P1 and P2. Metabolic evaluations revealed low prolidase enzyme activity in P1 and P2. Conclusion: Beyond the well-known classical dermatological findings, the presence of recurrent opportunistic infections, gastrointestinal involvement, malignancy, and flow cytometry findings suggestive of combined immunodeficiency indicate that the diagnosis of prolidase deficiency may be underestimated. Knowing the atypical and rare presentations will facilitate diagnosis and treatment of affected patients.