Currarino Syndrome in Two Moroccan Siblings with Inherited 7q36 Deletion due to Maternal t(7;21)(q36;p11)mat: A Case Report

Abstract

Introduction

Currarino syndrome is a rare syndrome with multiple congenital anomalies including sacral agenesis, anorectal malformation, and presence of a presacral mass. Currarino syndrome is considered to be an autosomal dominant inherited disorder, with low penetrance and variable expressivity, but sporadic cases have also been reported. Mutations in MNX1 gene, mapped to 7q36, are the main causes of this syndrome. To the best of our knowledge, less than 400 cases of this syndrome have been mentioned in the literature. Currarino syndrome is often seen in children and considered to be rare in adults; it is mostly found as incidental finding and suspected to be underdiagnosed.

Case Presentation

Recognizing the rarity of this syndrome, we present here two siblings with incomplete form of Currarino syndrome combined with microcephaly and intellectual disability. Banding and molecular cytogenetics were used to characterize the origin of this disorder. Banding cytogenetics together with molecular cytogenetics revealed an unbalanced translocation t(7;21)(q36.2;p11.3)mat, leading to a deletion of the 7q36 region in both affected children.

Conclusion

This report highlights the importance of cytogenetics in diagnosis of rare genetic syndromes, with impact on genetic counseling of patients and their families. To the best of our knowledge, this is the first Moroccan Currarino syndrome case due to an unbalanced translocation leading to a der(7)t(7;21)(q36.2;p11.3). Also, this is the first Currarino syndrome case associated with a deletion in 7q36 to be reported in Morocco.

Established Facts

• •Currarino syndrome is an autosomal dominant inherited disorder, with low penetrance and variable expressivity.
• •Currarino syndrome is a rare syndrome, with less than 250 cases reported, with multiple congenital anomalies including sacral agenesis, anorectal malformation, and presence of a presacral mass.

Novel Insights

• •Here, for the first time in Morocco, we report Currarino syndrome case associated with a deletion in 7q36.
• •The two siblings have the same deletion but different phenotypes.

Introduction

Currarino syndrome (CS) is a rare genetic disorder generated by haploinsufficiency of the motor neuron and pancreas homeobox 1 (MNX1) gene located on chromosome 7q36.3 (chr7:156,786,745-156,802,129; acc. to GRCh37). In 1981, Currarino [Yip et al., 2020] described as mandatory features of CS a triad of anorectal malformations, sacral bony defects, and presence of a presacral mass. CS shows a variable clinical spectrum, and is defined as “complete” if all three main identified features are present, and “incomplete” if one or more anomalies from the triad are absent making a diagnosis difficult. Thus, the true prevalence of the CS is hard to guess and has been estimated as 1 to 9 in 100,000 [YildirimTopaloğlu et al., 2014].

Typically, CS is due to autosomal dominant mutations in MNX1 gene [Pavone et al., 2010]. Large subtelomeric deletions in 7q36.3 have also been associated with CS patients; still these may have additional signs due to the loss of other genes [Horn et al., 2004]. Several incomplete forms of CS with variable phenotypes are described, since the only mandatory clinical feature for CS diagnosis is the sacral anomaly. Mutations in the MNX1 gene were identified in nearly all patients with a familial form of and 30% of those with a sporadic CS [Cococcioni et al., 2018].

The gene that is involved in this syndrome is MNX1 gene; it has 3 exons, encoding a protein of 403 amino acids, which is a key protein transcription factor. Further research has mentioned its role in normal regulation of the different stages of the early embryonic development of the caudal part [Belkacem et al., 2010].

Half of cases are due to an autosomal dominant mutation in the MNX1 gene. This gene is involved in development of the caudal end of embryo, and its mutations cause the abnormal separation of the neuroectoderm and endoderm before the development of the notochord. In the normal state, the endodermal layer (future digestive tube) closes at about the same time as the neural ectoderm (future neural tube) [Hage et al., 2019]. The notochord and the somites will form the future vertebral bodies, thus isolating the neural tube neural tube from the primitive intestine. The persistence of an abnormal connection between the endoderm and the neuroectoderm would prevent the anterior fusion of the vertebral body; this would create a “fistula” between the digestive and neural parts. The partial resorption of this “fistula” on the dorsal side would cause a meningocele and, on the ventral side, an enteric cyst. A teratoma would be formed if the enteric and neural elements remained linked by elements of the mesoderm having migrated into the presacral space during the development of the somites [Belkacem et al., 2010]. Here, we report two siblings with sacral agenesis combined with microcephaly, facial dysmorphism, overgrowth, and mental retardation with a terminal 7q36.2 deletion due to a balanced translocation in the mother.

Case Presentation

We report two siblings from unrelated parents referred for isolated partial agenesis of the coccyx involving sacral vertebrae S2–S5 and other clinical signs (see Table 1). Both parents were healthy and were never exposed to undesirable substances, such as poisons and radiation. The pregnancy was unfollowed and both cases were born as term infants via normal vaginal delivery. At birth, the 16-year-old boy weighed 4 kg (90th percentile) and measured 54 cm (90th percentile). During the last evaluation, his weight was 75 kg (97th percentile) and his height had reached 185 cm (97th percentile). The younger brother’s measurements were as follows: at birth, he weighed 3.8 kg (85th percentile) and measured 52 cm (85th percentile) in height. In the latest evaluation, his weight had increased to 70 kg (95th percentile) and his height was 175 cm (95th percentile). These measurements refer to a significant staturoponderal excess (overgrowth) for both siblings.

Table 1.

Features of patients with CS

Age at diagnosis	Gender	CS	Features	Chromosomal abnormality	De novo or inherited	Other familial cases	Reference
3 yr	F	Complete	Currarino triad including microcephaly and sensorineural deafness	Duplication-deletion of distal 7q	De novo	No familial cases	Pavone et al., 2010
5 yr	F	Complete	Currarino triad, characterized by congenital anorectal stenosis, a sacral defect, and a presacral mass	Deletion 7q35-qter	De novo	No familial cases	Masuno et al., 1996
3 yr	F	Complete	CS features combined with microcephaly	Deletion of 7q36.2q36.3 region	De novo	No familial cases	Cococcioni et al., 2018
15 yr	M	Complete with variable phenotypes	Currarino triad and a number of nonspecific features of the CS consisting of moderate mental retardation, growth deficiency, feeding problems, and microcephaly	t(7;14)mat	Inherited	Maternally inherited	YildirimTopaloğlu et al., 2014
13 yr	F
16 yr	M	Incomplete with variable phenotypes	Sacral agenesis S2–S5, microcephaly, facial dysmorphism, and mental retardation	t(7;21)mat	Inherited	Maternally inherited	Our case
14 yr	M		Microcephaly, sacral agenesis S2–S5, low spinal cord syndrome, and school delay

CS, Currarino syndrome; F, female; M, male; yr, years.

Both siblings presented congenital microcephaly (32 cm), thick and arched eyebrows, and a nose resembling a beak with a prominent columella. However, the older sibling, 16 years old, additionally exhibits a mild facial dysmorphism characterized by a long face. He also exhibits severe intellectual disabilities compared to his 14-year-old brother, who faces only challenges in his academic performance. Cranial magnetic resonance imaging revealed low spinal cord syndrome attached.

Methods and Results

Parents gave informed consent for this study, which was performed in accordance with the Declaration of Helsinki protocols and approved by the Local Institutional Review Boards. Venous blood (3–5 mL) acquired in a heparinized tube was taken from the patients and the parents for cytogenetic studies. First, chromosomal analysis was performed by R-banding. Thereafter, considering the co-occurrence of a CS-like phenotype and microcephaly with terminal 7q deletion reported in literature, fluorescence in situ hybridization (FISH) technique was performed, applying homemade whole chromosome painting probes for chromosomes 7 (wcp7) and a LSI probes specific to 7q36 region (RP5-1015024). FISH experiments confirmed the presence of a 7q36 deletion in the two brothers (Fig. 1a). Then, both classical and molecular cytogenetic techniques are used to investigate if there is a balanced chromosomal rearrangement in both parents at the origin of this deletion. The parents’ karyotype showed no clear aberrations (Fig. 2). Molecular cytogenetic FISH techniques with a simultaneous use of multi-probes: the RP11-49G5 specific to 7q35 region, RP5-1015O24 specific to 7q36.3 region, and ST7qter specific to the telomeric region 7qter. The test did not provide any abnormality in the father (Fig. 1c); while in the mother, the probes RP5-1015O24 and ST7qter have been hybridized on the short arm of chromosome 21 (Fig. 1b1), so it’s a derivative chromosome 7 on chromosome 21 and it is probably a balanced reciprocal translocation between chromosome 7 and 21. To confirm this hypothesis, we have applied a multi-FISH with 4 probes: whole chromosome painting probes for chromosome 7 (wcp7), whole chromosome painting probes for chromosome 21 (wcp21), a midi 54 probes for all acrocentric chromosomes, and the ST7qter specific to the telomeric region 7qter. FISH experiment shows a derivative of chromosome 21 on chromosome 7 thus confirming the balanced translocation (7,21) in the mother (Fig. 1b2).

Fig. 1.

Result of molecular cytogenetics for the presented family.

Fig. 2.

The karyotype of the parents showing no chromosomal aberration.

Our investigation by M-FISH found a deletion in the 7q36.3 region including the MNX1 gene, responsible for the CS. Analysis of the parents reveals a balanced reciprocal translocation in the mother, classified as t(7;21)(q36.2;p11.3)mat.

Discussion

CS patients show a broad phenotypic variability. Patients with CS can be diagnosed in the neonatal period, but the diagnosis is usually made late in childhood, due to the fact that the lesion may still be asymptomatic or manifested by nonspecific symptoms such as constipation, rectal fullness, urinary symptoms such as dysuria due to local pressure effect, lower abdominal pain, and meningitis [Vitale et al., 2020].

Deletions of the 7q36 region have been reported in association with CS and other signs. In the present case, CS was due to a terminal deletion of 7q36 due to a maternally inherited unbalanced translocation involving chromosomes 7 and 21. A review of the literature on similar patients reported with CS is summarized in Table 1. Of 7 cases of deletions reported in literature, 3 were de novo, 4 familial. Familial cases were due to different chromosomal translocations but our family is the first reported 7q36-21p translocation. As well as in our case, patients with deletion involving the same region have shown elements of Currarino triad and microcephaly as main features. However, the other cases have also reported growth retardation, facial dismorphies, and other anomalies.

Most interesting thing in our family case is that the great phenotypic variability: two siblings with incomplete form of CS due to a pure 7q36 deletion but different dysmorphic characteristics. In our patients, the deletion of MNX1 should explain the CS, while the loss or gain of other genes is probably responsible for other aspects of the phenotype; however, although the two siblings have same genotype, they have different dysmorphic characteristics.

In summary, the Currarino triad seems to have genetically heterogeneous features. Recognizing the high risk of recurrence in familial cases, chromosomal analysis of patients and family members are essential whether they are symptomatic or asymptomatic. We report this case to increase awareness of occult existence of CS and to emphasize the importance of an early diagnosis to prevent future morbidity and mortality in patients with this syndrome.

Conclusion

CS is a rare disease, usually diagnosed at birth or prenatally, sometimes at a later age. Prenatal or preimplantation genetic diagnosis is possible with FISH in case of disease-causing microdeletion, which is rare in CS.

Acknowledgments

We thank the patient and his family.

Statement of Ethics

The whole pre-analytic and post-analytic steps described in this work were performed for patients by the Department of Medical Genetics of the National Institute of Health as medical services in agreement with the tenets of the Declaration of Helsinki. All ethical issues of the National Institute of Health in Rabat, Morocco, where the Department of Medical Genetics is housed, are under charge of an Intramural Advisory Committee. Written informed consent was obtained from the parents of the patient for publication of the details of their medical case and any accompanying images. Ethical approval was not required for this study in accordance with local/national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study had no funding source.

Author Contributions

Zhour El Amrani, Abdelhafid Natiq, Aziza Sbiti, and Maryem Sahli planned, performed the experiments, and wrote the manuscript. Maryem Sahli and Ilham Ratbi performed the clinical evaluation. Abdelhafid Natiq, Thomas Liehr, Aziza Sbiti, and Maryem Sahli planned, performed the experiments, and revised the manuscript.

Funding Statement

This study had no funding source.

Data Availability Statement

All data generated or analyzed during this study are included in this article.