Meacham syndrome
Meacham syndrome, also referred to as Meacham-Winn syndrome, is a rare congenital malformation complex that impacts multiple organ systems. Characterized by significant structural anomalies, it primarily affects the urogenital system, presenting features such as ambiguous genitalia, double or septate vagina, and retention of embryonic female structures in individuals with a male karyotype. Congenital heart defects and lung abnormalities are also common. The genetic basis of Meacham syndrome is linked to mutations in the Wilms' tumor-suppressor gene (WT1), although the specific causes and risk factors remain largely unknown, with cases appearing sporadically. Diagnosis typically requires molecular genetic analysis to identify mutations. Unfortunately, there is currently no established treatment, and affected individuals face high infant mortality rates due to the severity of associated malformations. Ongoing research into WT1-related disorders may eventually lead to advances in understanding and potential therapies.
Meacham syndrome
ALSO KNOWN AS: Meacham-Winn syndrome
DEFINITION Meacham syndrome is a congenital malformation complex that affects multiple organs and systems.
Risk Factors
There are no known risk factors for Meacham syndrome.
Etiology and Genetics
Reported cases of Meacham syndrome are rare (about thirteen, as of 2014, according to the US National Library of Medicine) and sporadic—that is, they occur randomly. It is the least characterized of several malformation syndromes associated with a mutation in the Wilms’ tumor-suppressor gene (WT1). Heterozygous missense mutations in two reported cases were shown to be within the short arm of chromosome 11 at band 13 (11p13).
The Wilms’ tumor-suppressor gene is so named because a mutation that inactivates its suppressor function confers a predisposition to Wilms’ tumor, a childhood malignancy arising in the kidney. The gene is mutated in 6 to 15 percent of sporadic cases of Wilms’ tumor, as reported by M. Sperling in Pediatric Endocrinology (2014). According to a 2011 Nature Reviews Cancer literature review by V. Huff, about one in 10,000 live births is affected.
The first report of Meacham syndrome, in 1991, described two unrelated infants with severely disordered structures of sexual differentiation: malformed female genitalia and other gonadal abnormalities in genetic males (having a 46,XY karyotype). The infants had other severe, multisystem malformations. The malformation pattern was unusual, with no attributable cause or etiology. Consanguinity, chromosomal anomalies, teratogenic exposure, and a family history of similar defects were ruled out.
The genetic underpinnings of Meacham syndrome must be understood in the context of the WT1 gene and its considerable role in development. Tumor-suppressor genes—WT1 is one of many—encode proteins that inhibit malignant with mechanisms that include regulating the and overseeing DNA replication. It can be inferred, therefore, that WT1 has multiple roles in mammalian embryonic development; it is known to be expressed in many tissues: among them, the urogenital system, spleen, diaphragm, heart, and areas of the central nervous system. That WT1 has a crucial role in normal urogenital development is widely accepted.
Given the complex functions of this gene, it follows that Meacham syndrome is not the only malformation complex that can result from a WT1 mutation. Several disorders with varying phenotypes are well documented. One of the first to be identified is linked to a deletion within one copy of 11p13. Known as the Wilms’ tumor-aniridia-genitourinary anomalies-mental retardation (WAGR) syndrome, its constellation of anomalies includes an estimated 45 percent probability of developing Wilms’ tumor, according to the National Library of Medicine.
Denys-Drash syndrome is a severe disorder with some clinical features overlapping those of Meacham syndrome. It is identified with a heterozygous, dominant-negative mutation at 11p13. In this type of mutation, the abnormal protein that results overrides the function of the normal protein produced by the corresponding allele. A high risk of Wilms’ tumor, varying degrees of genital and gonadal anomalies, and early kidney failure are characteristic features of the Denys-Drash syndrome. Tumor-suppressor capabilities are lost. One reported case suggested that the WT1 mutation may be incompletely penetrant; the mutant allele was inherited from the infant’s father, who was phenotypically unaffected.
Still another related disease is Frasier syndrome, which is attributed to a splice mutation. Rather than producing a mutant protein, the WT1 disrupts alternative splicing, leading to a skewed balance of WT1 isoforms. The typical patient with Frasier syndrome is an adolescent with female external genitalia, abnormal gonadal development, and a male karyotype. Kidney function generally progresses to end-stage renal disease by adolescence or early adulthood, although Wilms’ tumor is not a usual feature.
On the molecular level, the human WT1 gene spans about fifty kilobases and comprises ten exons (coding sequences). The WT1 gene product is a nuclear protein known as a transcription factor. Transcription factors regulate expression of many target genes by binding with their DNA; WT1 is also believed capable of binding messenger RNA (mRNA), thereby according it a further role in processing. The result, ultimately, is numerous proteins that control cellular phenotypes and regulate growth. In the event of gene deletion or mutation, what follows is a cascade of dysfunctional effects on developing tissues.
The syndromes produced by aberrations in the WT1 gene must be defined by molecular analysis rather than by clinical phenotype, underscoring the increasing importance of in clinical practice.
Symptoms
Meacham syndrome has characteristic multisystem malformations: urogenital anomalies may include a double or septate vagina, ambiguous genitalia, and retention of Müllerian (embryonic female) structures, together with a male karyotype. Congenital heart defects, a hypoplastic lung or left heart, and congenital diaphragmatic hernias are also reported.
Screening and Diagnosis
Meacham syndrome may be suspected in an infant given the presence of characteristic anomalies, but diagnosis can be confirmed only by molecular genetic analysis. Most cases of diaphragmatic malformations, however, can be diagnosed before birth.
Treatment and Therapy
Other than supportive care for affected infants, there is no known treatment for Meacham syndrome. Research into the multiple conditions associated with WT1 genetic mutations has been ongoing, however, and advances in genetic study and gene therapy could provide more options in the future.
Prevention and Outcomes
The occurrence of sporadic syndromes cannot be prevented by known means. The severe malformations that characterize Meacham syndrome are not consistent with life. Diaphragmatic abnormalities alone confer considerable infant mortality, and other structural anomalies worsen the prognosis. Reported cases have died in early life.
Bibliography
Dolan, Siobhan M. "#608978 Meacham Syndrome." OMIM.org. Johns Hopkins U, 21 July 2009. Web. 1 Aug. 2014.
Huff, Vicki. "Wilms' Tumours: About Tumour Suppressor Genes, An Oncogene and a Chameleon Gene." Nature Reviews Cancer 11.2 (2011): 111–21. PDF file.
Kniffin, Cassandra L., et al. "*607102 WT1 Gene; WT1." OMIM.org. Johns Hopkins U, 23 Jan. 2013. Web. 1 Aug. 2014.
Lopez-Gonzalez, M., Ariceta, G. WT1-Related Disorders: More than Denys-Drash Syndrome. Pediatric Nephrology, vol. 39, pp. 2601–2609, Sept. 2024, doi.org/10.1007/s00467-024-06302-y. Accessed 9 Sept. 2024.
Nussbaum, Robert L., Roderick, R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Sperling, Mark A. Pediatric Endocrinology. 4th ed. Philadelphia: Elsevier, 2014. Digital file.
"WT1." Genetics Home Reference. US Natl. Lib. of Medicine, Mar. 2013. Web. 1 Aug. 2014.