The clinical overlap between cardiac‐urogenital syndrome, Meacham syndrome, and PAGOD syndrome. Report of a new patient with cardiac‐urogenital syndrome

Abstract

We have read with great interest the article "Review of the phenotypic spectrum associated with haploinsufficiency of MYRF" by Rossetti et al. published in The American Journal of Medical Genetics (2019;179A: 1376-1382) (Rossetti et al., 2019). We want to congratulate the authors on their review and make some contributions. We report a de novo novel pathogenic variant on the MYRF gene consistent with the reported phenotype of cardiac-urogenital syndrome and reflect on phenotypical similarities between this new syndrome and the previously described Meacham syndrome.Our patient is a male born by caesarean section at 40 weeks of gestational age to nonconsanguineous healthy 32-year-old mother and 30-year-old father. He had a birth weight of 3060 g (15th-50th percentile), length of 49 cm (15th-50th percentile), and head circumference of 35.3 cm (50th-85th percentile), and his Apgar score was 10 at the first minute and at the fifth minute. He had a micropenis, hypospadias, and bilateral cryptorchidism. No dysmorphic facial or limb anomalies were apparent. Hypoplastic left heart syndrome was diagnosed in the first day of life by cardiac ultrasound. He underwent palliative cardiac repair-Norwood 1 procedure in his first week of life, Glenn procedure at 5 months, and Fontan procedure at 5 years of age. Hypospadias correction was done at 2 years of age, bilateral orquidopexy and penile reconstruction at 4 years of age. The left testicule was atrophied and a left orquidectomy along with testicular prothesis insertion was performed at 10 years old. All surgeries and respective postoperative care were uneventful. He had normal growth and normal puberty onset, and follow up in endocrinology showed that hormonal substitution therapy was unnecessary. He has had no post-Fontan procedure complications. He showed severe developmental delay since infancy and has needed early intervention, as well as occupational therapies and special education throughout his life.Motor skills were achieved fairly within the normal range. Brain magnetic resonance imaging (MRI) at 4 years of age showed signs of delayed myelination. There were no structural alterations. At 17 years old, he has profound cognitive impairment with an intelligence quotient evaluation of 20. He was diagnosed with moderate bilateral hypermetropy at 6 years of age and has since then used corrective lenses.DiGeorge and Smith-Lemli-Opitz syndromes were excluded shortly after birth. Array comparative genomic hybridization was normal.

Two sisters with cardiac‐urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism?

“…He was further described to have cognitive impairment with an intelligence quotient score of 20. At 4 years of age, brain magnetic resonance imaging showed signs of delayed myelination (Alves & Leão, 2020). The patient's neurological impairment was reported as well by Pinz et al, who described one patient with speech delay who lived until 18 months, and Qi et al, who reported a 2‐year‐old with intellectual disability and motor delay (Pinz et al, 2018; Qi et al, 2018).…”

MYRF: A unique transmembrane transcription factor‐ from proteolytic self‐processing to its multifaceted roles in animal development

“…[7,[34][35][36]41,42] Additionally, it presents with a wide spectrum of developmental delay and intellectual disability, pulmonary abnormalities, diaphragmatic issues, and intestinal malrotation. [41,[43][44][45][46][47][48] Many aspects of these developmental processes remain incompletely understood, and the causes of abnormal development are not well-established. A pathogenic variant of MYRF is also associated with neurological conditions characterized by extensive myelin vacuolization, reflecting similar findings observed in mice where Myrf plays a crucial role in regulating myelination.…”

“…DD and ID encompass a broad spectrum of conditions, ranging from mild speech delays to severe developmental delays and cognitive impairment. [7,41,43] The severity and prevalence of these conditions can be influenced by the presence of cardiopulmonary defects.…”

“…The majority of reported individuals with sex-related phenotypes exhibit a 46,XY karyotype, and the genitourinary anomalies encompass a wide range. [7,34,40,41,[43][44][45][46] They may involve underdeveloped male sexual organs, such as cryptorchidism (undescended testicles), microphallus (abnormally small penises), small testes, hypospadias (urethra opening on the underside of the penis), chordee (abnormal bending of the penis), bifid scrotum (two separate scrotums), and/or a persistent urachus (a tube in fetal development that connects the urinary bladder to the umbilicus, normally closing before birth). Conversely, some female structures may be present, including the uterus and vagina (typically hypoplastic), which originate from Müllerian tubules.…”

“…The spectrum of cardiovascular anomalies is extensive, with Scimitar syndrome being a commonly reported condition. [7,40,41,43,44,46,48] This syndrome is characterized by an abnormal placement and structure of the pulmonary veins. Instead of connecting to the left atrium as expected, one or more pulmonary veins from the right lung drain into the inferior vena cava or the right atrium.…”