Autosomal Dominant Transmission Reframes Reproductive Counseling in Myhre Syndrome: A Novel Family and Literature Review.

Myhre syndrome is a rare multisystem genetic disorder that is caused by de novo heterozygous gain-of-function variants in SMAD4. Patients with Myhre syndrome exhibit several phenotypes at different ages such as small size, autism, developmental delay, left-sided heart defects, and hearing loss and often have a characteristic facial appearance. The early clinical diagnosis of Myhre syndrome remains a major challenge, particularly in the first year of life. A Chinese male infant with syndactyly of fingers, hypertelorism, short palpebral fissures, and short philtrum was enrolled into the ENT department of the Chinese PLA General Hospital. Whole exome sequencing analysis was used to detect the disease-causing variant. A literature review of Myhre syndrome was also performed. A recurrent de novo missense variant c.1498A > G p.I500V(p. Ile500Val) in SMAD4 was detected confirming the clinical diagnosis of Myhre syndrome at the age of 38 days. The infant appears to be the youngest reported case of Myhre syndrome. At 23-month follow-up, the affected infant has dysmorphic facial features, growth retardation, and previously undescribed complete syndactyly. Review the literatures noted several common features in Myhre syndrome patients including hearing loss (72.7%), characteristic facial features (26.0%-54.5%), finger and toe abnormalities (3.9%-48.1%), short stature (45.5%), and respiratory (30.0%) and cardiovascular problems (65.0%). Clinicians should have a low threshold to perform genetic testing on patients with features suggesting Myhre syndrome even in the first year of life. Although some individuals with Myhre syndrome have normal hearing, early onset or progressive hearing loss usually occur in one or both ears in most patients, with remarkable phenotypic heterogeneity. Syndactyly may be minor such as typical 2-3 toe involvement, or more complicated as was observed in our patient.

Myhre syndrome is a rare multisystem disorder characterized by distinctive facial features, hearing loss, and progressive fibrosis affecting the skin, joints, lungs, and cardiovascular system. It is caused by heterozygous pathogenic variants in the SMAD4 gene. In this review, we detail the cutaneous manifestations observed in two previously reported patients with genetically confirmed Myhre syndrome. While skin biopsies demonstrated pan-dermal thickening of collagen bundles, the immunohistochemical staining patterns were distinct from those seen in other inflammatory sclerosing disorders. Additionally, we conducted a comprehensive literature review of the cutaneous features associated with Myhre syndrome, identifying 175 patients with confirmed SMAD4 pathogenic variants. The most reported cutaneous finding was thickened or stiff skin (76%), followed by keratosis pilaris (22%) and impaired wound healing or abnormal scarring (18%). Genotype-phenotype analysis suggested a diagnostic delay in patients with the codon 496 variant, who were more frequently diagnosed in adulthood. This variant may also be associated with a milder cutaneous phenotype, highlighting the clinical heterogeneity of Myhre syndrome. These findings underscore the importance of recognizing cutaneous features as potential early diagnostic clues in patients with suspected Myhre syndrome.

SummaryWhile it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These “selfish” mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father’s age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor’s age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity

Myhre syndrome is a rare genetic autosomal dominant connective tissue disorder, characterized by developmental delay, characteristic facial features, various bone and joint abnormalities, distinctive cardiovascular, ophthalmological and ear, nose and throat (ENT) manifestations, in association with mild to moderate intellectual disability and autism or autism spectrum disorder-like behaviour. The diagnosis of Myhre syndrome is established corroborating the clinical findings with SMAD4 heterozygous mutation identified in the majority of the patients. SMAD4 gene mutations result in abnormal TGF-β signalling in several cell types, which affects the development of several body systems and leads to the specific phenotype of Myhre syndrome. We herein report the case of an 18-year-old female patient who was diagnosed at the age of 17 years with Myhre syndrome, the first documented case of this syndrome in Romania. Sequence analysis of protein-coding genes using whole-exome analysis identified a ‘de novo’, heterozygous missense variant of SMAD4, c.1498A>G, p. (Ile500Val), which is pathogenic for Myhre syndrome. Although this condition is rare, a series of particularities were identified in the present case, consisting of severe allergic reactions, recurrent ENT tumour development and delayed dental eruption, which have not been described in Myhre syndrome to date, to the best of the authors' knowledge.

Background: Myhre syndrome is a rare connective tissue disorder caused by heterozygous pathogenic variants in the SMAD4 gene. Although recognizing Myhre syndrome in early childhood is challenging, it is important to manage airway stenosis in patients with Myhre syndrome. Case Presentation: We report the case of a 2-month-old boy who initially presented with severe multilevel airway stenosis, dysmorphic face, and multiple abnormalities. Lung fibrosis and mild aortic valve stenosis were additionally observed on follow-up examinations. A heterozygous missense variant, c.1499T>C (p.Ile500Thr), in SMAD4 was identified through exome sequencing. Tracheostomy was performed, and the patient has maintained stable respiration through a customized tracheostomy tube with a home ventilator. Conclusions: Patients who have dysmorphic face, airway stenosis, and cardiovascular anomalies that do not fit the diagnosis of common syndromes should be evaluated for rare diseases, including Myhre syndrome. Since respiratory complications can be life threatening, early diagnosis and suitable intervention are necessary.

Myhre syndrome is a rare progressive genetic disorder characterized by hearing loss, cardiovascular and joint problems, neoplasia, and neuropsychologic disabilities. Parents of children with Myhre syndrome and adults themselves face unique challenges, stresses, and fears associated with this diagnosis. Reflective writing in the form of journaling can provide psychosocial support and help individuals cope with this diagnosis. Adult patients and parents whose children were evaluated at the Massachusetts General Hospital Myhre Syndrome Clinic were invited to participate in a three-month journaling intervention. Participation in the study required the completion of a series of surveys prior to starting and upon completion of the study. Data from these surveys were analyzed to assess for change in mental well-being. Eleven individuals participated, six of whom completed the three-month journaling intervention and post-journaling surveys. Three participants indicated that journaling had an impact on their mental well-being, and of these, two planned to continue journaling. However, there was no statistically significant difference in mental well-being scores pre- and post-journaling intervention. The very small size of the study limits interpretation, but we think it is reasonable to suggest that expressive writing through journaling may be a coping mechanism and means of improving well-being for some individuals in the Myhre syndrome community.

Pregnancy loss can have physical and psychological consequences for women and their families. Though a previous study described an increase in the risk of self-reported pregnancy loss from 1970 to 2000, more recent examinations from population-based data of US women are lacking. We used data from the 1995, 2002, 2006-2010, 2011-2015 National Survey of Family Growth on self-reported pregnancy loss (miscarriage, stillbirth, ectopic pregnancy) among US women (15-44years) who reported at least one pregnancy conceived during 1990-2011 that did not result in induced termination (n=20012 women; n=42526 pregnancies). Trends in the risk of self-reported pregnancy loss and early pregnancy loss (<12weeks) were estimated, separately, by year of pregnancy conception (limited to 1990-2011 to ensure a sufficient sample of pregnancies for each year and maternal age group) using log-Binomial and Poisson models, adjusted for maternal- and pregnancy-related factors. Among all self-reported pregnancies, excluding induced terminations, the risk of pregnancy loss was 19.7% and early pregnancy loss was 13.5% during 1990-2011. Risk of pregnancy loss increased by a relative 2% (rate ratio [RR] 1.02, 95% confidence interval [CI] 1.01, 1.02) per year in unadjusted models and 1% per year (RR 1.01, 95% CI 1.00, 1.02) during 1990-2011, after adjustment for maternal characteristics and pregnancy-related factors. In general, trends were similar for early pregnancy loss. From 1990 to 2011, risk of self-reported pregnancy loss increased among US women. Further work is needed to better understand the drivers of this increase in reported pregnancy loss in the US.

Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.

Myhre syndrome is a rare disorder caused by a heterozygous mutation in the SMAD4 gene. Affected patients may exhibit dysmorphic facial features, intrauterine growth retardation, short stature, obesity, muscle hypertrophy, thickened skin, limited joint movement, hearing impairment, and varying degrees of psychomotor developmental disorder. Serious complications of the cardiovascular and respiratory system may be seen later in life. We report the case of a Chinese boy with Myhre syndrome presenting with a novel symptom of giant testicles where treatment with growth hormone combined with letrozole successfully improved his short stature. This case shows that letrozole combined with growth hormone can improve height in children with Myhre syndrome without adverse effects.

Myhre syndrome is a rare disorder caused by pathogenic gain-of-function variants in the SMAD4 gene. Most of the patients have had de novo variants. There are several instances of autosomal dominant inheritance, and penetrance appears to be complete. We describe seven Brazilian patients, three of whom are siblings carrying the recurrent c.1486C>T p.(Arg496Cys) variant in SMAD4 inherited from the father. The other three patients are unrelated simplex cases. All affected individuals have clinical features commonly found in Myhre syndrome, including typical dysmorphic facial features, with intra- and interfamilial clinical heterogeneity. Five of the patients have developmental delay and/or clinical signs of intellectual disability. However, only one had neuropsychological testing. Only one patient had a diagnosis of autism spectrum disorder. As in previously reported families, this new family has the same c.1486C>T p.(Arg496Cys) variant. This is the first study describing Brazilian patients with Myhre syndrome, highlighting the clinical variability of this rare disease. We reinforce the need to investigate the parents to provide appropriate genetic counseling.

Study question Is endocrine disease and pregnancy loss associated, and can the association be due to inherited genetic causes? Summary answer Endocrine disease is associated with an increasing number of pregnancy losses. Endocrine disease in parents and siblings increases a woman’s risk of pregnancy loss. What is known already One in four pregnancies results in a pregnancy loss, but only 60% hereof are due to detectable chromosome abnormalities. The remaining 40% are suspected to be caused by other factors such as maternal comorbidity. Recurrent pregnancy loss (RPL) is defined as 2 or 3 consecutive losses and affects 1-3% of couples trying to conceive. Pregnancy loss has been associated with endocrine diseases, e.g., thyroid disease, diabetes, or PCOS. Furthermore, thyroid autoimmunity has been associated with RPL. It is unknown if other endocrine diseases are associated with RPL. To date, there is no evidence for a genetic basis of the risk. Study design, size, duration Danish nationwide cohort study including data from the Danish National Health Registers on ICD-8/ICD-10 diagnosis codes, all pregnancy outcomes and redeemed medicine prescriptions. Endocrine disease was defined as any endocrine disease (e.g., diabetes, thyroid disease, PCOS etc.). The study included in total 366,548 women, including 54,394 women with endocrine disease and 312,154 without endocrine diseases. The study included data from 1973 to 2022. Linkage to parent and siblings was available through the Multi-Generation Registry Lite. Participants/materials, setting, methods The cohort consisted of women born between 1977-1993 with ≥1 pregnancy. The exposure was endocrine disease. Logistic regression models adjusted for birth year provided odds ratios (ORs) for endocrine diseases according to number of pregnancy losses. Parent-offspring and sibling regression provided estimates for familial aggregation, assessing the degree of resemblance between relatives to infer the potential influence of shared familial factors. The variance-covariance matrix was adjusted using the Huber-White method to account for familial clustering. Main results and the role of chance We found a significant association between endocrine disease and pregnancy loss increasing with the number of pregnancy losses; OR and 95%CI for one loss 1.15 (1.12-1.17), two losses 1.31 (1.24-1.38) and ≥ three losses 1.81 (1.70-1.93). Further, endocrine disease was associated with RPL (OR 1.87, (1.74-2.00)). The association was strongest with primary RPL (OR 2.13 (1.94-2.35)), compared to secondary RPL (OR 1.58 (1.42-1.76)). In cases where either of a woman’s parents was diagnosed with an endocrine disease, she also had a higher risk of pregnancy loss (OR 1.06 (1.04–1.08)) and RPL (OR 1.07 (1.01–1.14)), compared to a woman with parents without endocrine disease. If a woman’s sibling had an endocrine disease, the OR for pregnancy loss was 1.07 (1.03–1.11) and RPL 1.17 (1.03–1.33). Further stratification into individual endocrine phenotypes revealed that type 2 diabetes conferred a comparable risk: for offspring of parents with this condition, the risk of pregnancy loss increased to an OR of 1.08 (1.06–1.11), and for siblings, the OR was 1.13 (1.02–1.25). This effect persisted even when adjusting for the disease in the individual experiencing the loss. Limitations, reasons for caution Very early pregnancy losses are often not handled at the hospital and therefore not part of the Danish registers. Thus, there is a risk of underdiagnosed pregnancy losses, although this would be the case for both the exposed and control cohort. Wider implications of the findings Women with RPL should be investigated for endocrine disease, and family history of endocrine disease is an important and novel risk factor that should guide the diagnostic work-up. Identifying the shared mechanism or pleiotropic effects between pregnancy loss and endocrine disease should be a focus area. Trial registration number Research related to this project was supported by the Novo Nordisk Foundation (ID: NNF22OC0077221, NNF23OC0087269) and the William Demant Foundation (salary for Pia Egerup).

Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients. Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity. • The clinical and radiological signs of the disease in children older than 7-8years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.

Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2‐year‐old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.

SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-β signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndrome. Whole-exome sequencing of a patient referred to our International Registry of Werner Syndrome revealed a heterozygous p.Arg496Cys variant of the SMAD4 gene. To investigate the role of SMAD4 mutations in accelerated senescence, we generated cellular models overexpressing either wild-type SMAD4 or mutant SMAD4-R496C in normal skin fibroblasts. We found that cells expressing the SMAD4-R496C mutant exhibited decreased proliferation and elevated expression of cellular senescence and inflammatory markers, including IL-6, IFNγ, and a TGF-β target gene, PAI-1. Here we show that transient exposure to TGF-β, an inflammatory cytokine, followed by chronic IFNγ stimulation, accelerated rates of senescence that were associated with increased DNA damage foci and SMAD4 expression. TGF-β, IFNγ, or combinations of both were not sufficient to reduce proliferation rates of fibroblasts. In contrast, TGF-β alone was able to induce preadipocyte senescence via induction of the mTOR protein. The mTOR inhibitor rapamycin mitigated TGF-β-induced expression of p21, p16, and DNA damage foci and improved replicative potential of preadipocytes, supporting the cell-specific response to this cytokine. These findings collectively suggest that persistent DNA damage and cross-talk between TGF-β/IFNγ pathways contribute to a series of molecular events leading to cellular senescence and a segmental progeroid syndrome.