Introduction: Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer than 100 patients were reported until recently, and all molecularly confirmed cases had de novo heterozygous gain-of-function mutations in the SMAD4 gene. Dysregulation of the TGF-beta signaling pathway leads to axial and appendicular skeleton, connective tissue, cardiovascular system, and central nervous system abnormalities. Case Presentation: Two siblings, 12 and 9 years old, were referred to us because of intellectual disability, neurodevelopmental delay, and dysmorphic facial features. Physical examination revealed hypertelorism, strabismus, small mouth, prognathism, short neck, stiff skin, and brachydactyly. Discussion: With a clinical diagnosis of MS, the SMAD4 gene was analyzed via Sanger sequencing, and a heterozygous c.1486C>T (p.Arg496Cys) pathogenic variation was detected in both of the siblings. The segregation analysis revealed that the mutation was inherited from the father who displayed a milder phenotype. Among the 90 patients in the literature, one family was reported in which two siblings carried the same variation (p.Arg496Cys), inherited from the severely affected mother. We are reporting the second family which has three affected family members, a father and two children. We report this study to remind the clinicians to be aware of the parental transmission of SMAD4 variations and also evaluate the parents of the Myhre cases.

Established Facts

  • Myhre syndrome is caused by gain-of-function pathogenic variations in the SMAD4 gene.

  • Myhre syndrome is a connective tissue disorder characterized by intellectual and social disability, dysmorphic facial features, short stature, brachydactyly, and muscle pseudohypertrophy.

Novel Insights

  • This is the second reported family with Myhre syndrome caused by the same SMAD4 pathogenic variation.

  • Myhre syndrome may be an overlooked diagnosis in people with mild intellectual disability who are able to reproduce.

Myhre syndrome (MS) was first described as a growth deficiency syndrome in 1981 by Myhre et al. [1981]. MS is a connective tissue disorder characterized by intellectual disability, dysmorphic facial features, short stature, brachydactyly, and muscle pseudohypertrophy [Starr et al., 1993]. Progressive proliferative fibrosis may develop spontaneously or following a trauma [Meerschaut et al., 2019]. This may cause skin stiffening, limiting joint mobility, and may increase the risk for life-threatening complications such as laryngotracheal stenosis [Myhre et al., 1981; Michot et al., 2014; Lin et al., 2016]. MS is caused by gain-of-function mutations in the SMAD4 gene [Caputo et al., 2012; Le Goff and Cormier-Daire, 2012]. SMAD4 encodes the SMAD4 protein which has two functional domains known as Mad Homology domain 1 (MH1) and Mad Homology domain 2 (MH2). MH1 is a highly conserved DNA-binding domain. MH2 domain is required for transcriptional activation and interactions with the other Smad proteins [Le Goff et al., 2011]. Mutations in the MH2 domain result in perturbed expression of both TGF-β and BMP target genes, affecting the cell growth and differentiation [Li et al., 2020; Li and Wu, 2020]. Only four distinct SMAD4 missense pathogenic variants affecting the 496 and 500 residues located in MH2 domains have been detected in MS cases [Caputo et al., 2012; Le Goff and Cormier-Daire, 2012; Caputo et al., 2014; Meerschaut et al., 2019]. Fewer than 100 affected individuals with molecularly confirmed diagnosis have been reported [Starr et al., 1993; Titomanlio et al., 2001; Le Goff et al., 2014; Dolivo et al., 2017; Nomura et al., 2017; Alagia et al., 2018; Erdem et al., 2018; Meerschaut et al., 2019; Yu et al., 2019; Alape et al., 2020; Gürsoy et al., 2020; Lin et al., 2020; Cappuccio et al., 2022; Yang et al., 2022]. This study reports the second family demonstrating MS cases.

Patients were evaluated with detailed anamnesis and pedigree analysis. Biochemical and metabolic tests and imaging studies were performed.

Karyotype analysis was performed via G-banding following 72 h of cell culture from peripheral blood lymphocytes. Blood samples from the patients and their parents were collected using vacuum-EDTA tubes. DNA was isolated from the peripheral blood using QIAamp DNA Blood Mini Kit (Qiagen) following the manufacturer’s protocol. Quantification of DNA concentration and purity assessment was carried out by spectrophotometric methods. Agilent Oligonucleotide Microarray 8 × 60K was used for molecular karyotyping. The results were analyzed in Agilent Cytogenomic Edition 2.5.8.1/GRCh 37/HG19 analysis program. All coding exons and exon-intron regions of the SMAD4 gene were sequenced using next-generation sequencing technology (Miseq, Illumina Inc., San Diego, CA, USA).

Patient 1

The proband, a 12-year-old male, was referred to us due to mental retardation, obesity, and dysmorphic facial appearance. He was born after an uneventful pregnancy at term via spontaneous vaginal delivery. Birth weight was 2,710 g (1.5 SD), height was 47 cm (1.3 SD), and head circumference was 33 cm (1.3 SD). According to the parents’ statement, his developmental milestones had been delayed; he had started sitting at the age of 1 year, walking at the age of 2 years, and speaking his first sentences at the age of 2 years. When the patient was evaluated at our clinic, he could not talk at all, and there was no verbal communication, just meaningless noises. Physical examination revealed a narrow forehead, flattened nasal root, hypertelorism, strabismus, short philtrum, thin upper lip, small mouth structure, prognathism, short neck, small hands, brachydactyly, and skin thickening (shown in Fig. 1b, 2a). Repetitive clapping movements, limited eye contact, damaging behaviors were present. Due to these findings, the proband was referred to child psychiatry. He was diagnosed with autism. Because the proband was incompatible during the physical examination, joint openings could not be evaluated. His height was 161 cm (1.6 SD), head circumference was 58 cm (2.3 SD), and weight was 74 kg (2.3 SD). Metabolic analyses were normal. Complete blood count and biochemistry tests were within normal limits. No abnormalities were detected in abdominal USG, bone radiograph, cranial MRI, and transthoracic echocardiography.

Fig. 1.

a–c Photos of the father, the proband, and the sister, respectively. The three patients have the same dysmorphic facial features: narrow forehead, nasal root flattened and prominent, hypertelorism, short philtrum, small mouth structure, and prognathism.

Fig. 1.

a–c Photos of the father, the proband, and the sister, respectively. The three patients have the same dysmorphic facial features: narrow forehead, nasal root flattened and prominent, hypertelorism, short philtrum, small mouth structure, and prognathism.

Close modal
Fig. 2.

a, b Hand photos of the proband and sister of the proband; bilateral clinodactyly and thickening of the skin at the 5th finger are noticeable. c Proband’s father has scars that do not heal on right tibia extensor surface. d Image of the proband’s father’s bone radiograph. Radiographic evaluation of skeletal abnormalities revealed thoracic kyphosis, thoracic osteophytes, thoracic platyspondyly, enlarged interpeduncular distance, fused vertebrae at T4-T5 vertebral level.

Fig. 2.

a, b Hand photos of the proband and sister of the proband; bilateral clinodactyly and thickening of the skin at the 5th finger are noticeable. c Proband’s father has scars that do not heal on right tibia extensor surface. d Image of the proband’s father’s bone radiograph. Radiographic evaluation of skeletal abnormalities revealed thoracic kyphosis, thoracic osteophytes, thoracic platyspondyly, enlarged interpeduncular distance, fused vertebrae at T4-T5 vertebral level.

Close modal

Patient 2

The second patient, the sister of the first case, is a 9-year-old girl who was first referred to us at the age of 2 years and 10 months. She was born after an uneventful pregnancy at term by spontaneous vaginal delivery. Duodenal atresia and muscular-type VSD were detected at the examinations performed after birth. She underwent surgery for duodenal atresia; however, VSD has closed spontaneously in the follow-up period. Her developmental milestones and speech were delayed. Physical examination revealed similar findings to those of her brother: hypertelorism, strabismus, flattened nasal root, short philtrum, thin upper lip, prognathism, posteriorly rotated low ear, brachydactyly (shown in Fig. 1c, 2b). Her height, body weight, and head circumference were measured as 137 cm (1 SD), 63 kg (3.8 SD), and 56 cm (2.6 SD), respectively, at the age of 9 years. Metabolic and biochemical tests were found to be normal. The skull bones were thickened in radiological evaluation. Transthoracic echocardiography, cranial MRI, and abdominal USG were normal.

Patient 3

The third patient is the 38-year-old father of the proband. He was born by normal vaginal delivery at the 39th gestational week. He was the first child of healthy nonconsanguineous parents. There were no concerns after birth. Postnatal anthropometric measurements were unknown. Developmental milestones were reported to be normal. He was diagnosed with mild learning disability at the age of 10 years. After graduating from primary school, he did not go to high school and university. Since then, he worked at simple jobs which did not require high intellectual capacity. He has not been working at any job for the last 2 years. He reported delayed wound healing on the hands and legs beginning at the age of 20 years. He did not undergo a clinical evaluation for these complaints. Physical examination at the age of 36 years revealed facial dysmorphism including prominent forehead, hypertelorism, short philtrum, thin upper lip, narrow mouth, and prognathism (shown in Fig. 1a). Also, he had a short neck, obesity, brachydactyly, stiff skin on the extensor side of both hands. There was a restriction of movement in the hip, knee, and ankle joints. There were scars on the right leg that have not yet healed (shown in Fig. 2c). He was consulted with dermatology for a more detailed examination of the fibrotic scar tissue observed on the skin. In anthropometric measurements, height was 172 cm, head circumference was 60 cm, and weight was 130 kg. The body mass index was calculated as 43, indicating morbid obesity. Laboratory tests were found to be normal. Hearing loss was not detected, and the eye examination was normal. Radiographic evaluation revealed thoracic kyphosis, thoracic osteophytes, thoracic platyspondyly, enlarged interpeduncular distance, and fused vertebrae at T4-T5 vertebral level (shown in Fig. 2d)

The proband’s karyotype analysis was 46,XY, and aCGH result was normal. Since the proband had a typical dysmorphic facial appearance, global developmental delay, learning difficulties, and delayed wound healing, SMAD4 gene sequence analysis was performed with the preliminary diagnosis of MS. A heterozygous variation c.1486C>T, p.Arg496Cys was detected in the SMAD4 gene. The family screening revealed that the variation was inherited from the father to the siblings.

Fewer than 100 patients have been reported in the literature. Eighty cases were reported in a total of 27 studies. Thirty-five of these patients were male, and 45 of them were female. The ages of the reported cases ranged between 2 months and 55 years, and the median age was 18.7 years (summarized in Table 1). In MS patients, multisystem involvement and various complications are expected. Especially spontaneous or post-traumatic excessive fibrosis in airways can lead to stenosis and cause serious life-threatening complications [Oldenburg et al., 2015; Garavelli et al., 2016]. Therefore, an early diagnosis of these patients is very important in terms of preventing complications.

Table 1.

Comparison of the clinical characteristics of the Myhre syndrome patients in our family with those reported in the literature

 Comparison of the clinical characteristics of the Myhre syndrome patients in our family with those reported in the literature
 Comparison of the clinical characteristics of the Myhre syndrome patients in our family with those reported in the literature

Although the systemic involvement in patients with MS differs between the patients, dysmorphic facial features were observed in all patients [Li et al., 2020]. Common facial features of MS cases are short philtrum (90%), short palpebral fissures (86%), midface hypoplasia (82%), prognathism (82%), narrow mouth (78%) (summarized in Table 1). Although the dysmorphic characteristics of the proband’s father were apparent, we assumed that the father’s diagnosis was delayed because of his better mental capacity compared to his children. In this study, three cases within the same family shared the same pathogenic variation, but they had different presentations. This shows the importance of molecular examination in the diagnosis of MS since expressivity may vary and clinical findings may not be adequately informative for the diagnosis. Although the reason for variable expressivity of MS still remains unclear, epigenetic mechanisms are considered to be effective.

Furthermore, as we reported muscular VSD in our female patient, cardiovascular system findings can be observed in MS, such as VSD, aortic stenosis, and aortic coarctation. A variety of cardiovascular abnormalities were noted in 54% of the patients in the largest series of 32 patients [Michot et al., 2014]. Ophthalmological anomalies are another common feature of MS. Strabismus was detected in both siblings but not observed in the father in this study. Visual problems were reported in approximately half of the patients, in which the most common were refractory errors and strabismus; in a few patients, there was cataract, and increased intraocular pressure was reported in 1 patient [Yu et al., 2019]. Another commonly affected system is the gastrointestinal system. Our female patient had duodenal atresia. Michot et al. [2014] reported clinical findings in their review of 32 patients with MS, intestinal abnormalities (8/32), including duodenal atresia (1), esophageal stenosis (1), pyloric stenosis (1), gastritis (1), superior mesenteric artery syndrome (1), hepatomegaly (1), and chronic constipation (2).

Neoplasia was detected in 6 of 61 patients with MS recently. Endometrial cancer (3 cases, ages at diagnosis were 30, 36, 44 years, respectively), vestibular schwannoma (1, age at diagnosis was 26 years), optic nerve sheath meningioma (1, age at diagnosis was 17 years), and mesencephalic glioma (1, age at diagnosis was 17 years) were detected, and 4 of these 6 patients had p.Arg496Cys pathogenic variation [Lin et al., 2020]. TGFB-1 causes down-regulation of the tumor suppressor PTEN via activation of the SMAD4 and ERK1/2 pathway, which stimulates the migration of endometrial cancer cells [Xiong et al., 2016]. Pathogenic variants leading to gain of function in the SMAD4 gene may cause increased risk of endometrial cancer development [Lin et al., 2020]. We detected the same pathogenic variation in our 3 patients. It is crucial to be aware of the risk of malignancy and screen MS patients periodically for an early diagnosis.

Until 2019, reproductive capacity of the patients was unknown and fertility was never assessed [Lin et al., 2016]. In a study conducted in 2019, in which the first family with an affected mother and two siblings from the same family was published, the primary infertile female patient with MS became pregnant after assisted reproductive technique. It showed that patients with MS may have children by assisted reproductive technique [Meerschaut et al., 2019] (summarized in Table 1). Although there are adult MS patients in a wide serial report, there is no information about the fertility state of these patients [Le Goff et al., 2014]. To date, no MS case was reported with spontaneous pregnancy. In addition, as indicated in the first familial MS report, the need for repeated embryo transfers may be interpreted as reduced fertility is expected in MS cases. However, the cause of reduced fertility still remains unclear, and further studies are needed. Similar to our family, the p.Arg496Cys pathogenic variant was detected in the mother and her children in a Belgian family [Meerschaut et al., 2019]. These two families remind geneticists to provide reproductive counseling that fertility and reproduction are possible, currently, only for this variant. In addition, it is possible to speculate that even if the female MS cases have reduced fertility, males may be fertile. Our patient seems to be the first case reported as having normal fertility in the literature. This study contributes to the literature since we report the second familial MS cases and the first fertile MS case ever documented. Keeping in mind that the patients with MS can be fertile, providing prenatal genetic counseling is very important.

We thank the patients’ parents for their kind participation and support.

This study was performed in accordance with the Declaration of Helsinki principles. Written informed consent was obtained from the patient’s parents for the publication of this case report and accompanying images. As a result of the evaluation of the Ethics Committee of Marmara University, study approval statement was not required for this study in accordance with local/national guidelines.

The authors have no conflicts of interest to declare.

There are no funding sources to report.

Şenol Demir and Esra Arslan Ateş designed the study. Şenol Demir prepared the manuscript for the study. Ceren Alavanda made the patient’s physical examination. Ayça Dilruba Aslanger analyzed chromosome and aCGH. Gözde Yeşil and Esra Arslan Ateş critically reviewed the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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