Report on a Case with Moreno-Nishimura-Schmidt Overgrowth Syndrome: A Clinically Delineated Disease Yet of an Unknown Origin!

Abstract

Introduction

Overgrowth syndromes are a heterogeneous group of genetic disorders characterized by excessive growth, often accompanied by additional clinical features, such as facial dysmorphism, hormonal imbalances, cognitive impairment, and increased risk for neoplasia. Moreno-Nishimura-Schmidt (M-N-S) overgrowth syndrome is a very rare overgrowth syndrome characterized by severe pre- and postnatal overgrowth, dysmorphic facial features, kyphoscoliosis, large hands and feet, inguinal hernia, and distinctive skeletal features. The clinical and radiological features of the disorder have been well delineated, yet its molecular pathogenesis remains unclear.

Case Presentation

We report on a Lebanese boy with M-N-S syndrome, whose clinical manifestations were compared with those of previously reported 5 affected individuals. Whole-exome sequencing combined with comparative genome hybridization analysis failed to delineate the molecular basis of the phenotype. However, epigenetic studies revealed a different methylation status of several CpG sites between him and healthy controls, with methyltransferase activity showing the most significant enrichment.

Conclusion

An additional case of M-N-S syndrome recapitulated the clinical and radiological manifestations described in the previous reports. The data in the epigenetic studies implicated that abnormal methylations might play an essential role in development of the disease phenotype. However, additional studies in a clinically homogeneous cohort of patients are crucial to confirm this hypothesis.

Established Facts

• Overgrowth syndromes are a heterogeneous group of genetic disorders characterized by excessive growth, often accompanied by additional clinical features.

• A complex interplay of genetic, epigenetic, and/or hormonal factors can contribute to overgrowth syndromes.

• Moreno-Nishimura-Schmidt overgrowth syndrome is a very rare overgrowth syndrome that is clinically delineated but molecularly uncharacterized yet.

Novel Insights

• A Lebanese patient with Moreno-Nishimura-Schmidt (M-N-S) syndrome presenting with osteoporosis and mild intellectual disability is reported.

• Comparative genome hybridization array analysis was performed for the first time on a patient with M-N-S but failed to reveal the causative genetic aberration.

• Epigenetic studies revealed a difference in the methylation status of several CpG sites in the patient compared to controls, with methyltransferase activity showing the most significant enrichment.

Introduction

Overgrowth syndromes (OGSs) are a heterogeneous group of disorders characterized by increased growth parameters in addition to other variable features including facial dysmorphism, life-threatening hypoglycemia, hormonal imbalances, cognitive impairment, and increased risk for neoplasia [Lapunzina, 2005; Lacerda et al., 2014; Manor and Lalani, 2020]. Overgrowth can be generalized, leading to an increase in overall growth parameters, or localized/partial, affecting one or few body organs/segments [Welch, 2015; Kamien et al., 2018]. Some OGSs present with prenatal overgrowth features that can be postnatally progressive, while others show postnatal overgrowth that manifests in infancy and childhood or even in adolescence [Manor and Lalani, 2020].

A complex interplay of genetic, epigenetic, and/or hormonal factors can contribute to the disease [Cytrynbaum et al., 2019; Manor and Lalani, 2020; Mazziotti et al., 2022]. Constitutional and somatic aberrations of single genes are involved in global and localized overgrowth disorders, respectively. In addition, genomic imprinting abnormalities are the third mechanism of growth dysregulation [Tatton-Brown and Weksberg, 2013].

Among more than 15 different OGSs that have been recognized to date, Moreno-Nishimura-Schmidt (M-N-S) OGS, also known as endochondral gigantism or metaphyseal undermodeling, spondylar dysplasia, and overgrowth (MIM 608811), is a rare generalized OGS. The disorder is characterized by severe pre- and postnatal overgrowth, facial dysmorphism, kyphoscoliosis, and skeletal features, including hyperostosis of the skull base, spondylar dysplasia, and metaphyseal broadening [Moreno et al., 1974; Nishimura et al., 2004; Schmidt et al., 2007; Bonafe et al., 2015]. To date, 5 affected individuals have been reported [Moreno et al., 1974; Nishimura et al., 2004; Sadeghi-Nejad and Karlin, 2005; Schmidt et al., 2007; Handa et al., 2017]. Although the clinical and radiological features of the disease have been well delineated, its molecular basis and pathogenesis remain elusive. We report here on a Lebanese patient with M-N-S syndrome, including his thorough clinical description and radiological manifestations with comparison with those previously reported and epigenetic abnormalities on molecular examinations.

Case Report

The patient was a Lebanese boy who was born at term to his healthy, unrelated parents. Birth weight was 5,600 g, length 61 cm, and head circumference (OFC) 38.3 cm (all largely above the 97th percentile). He also showed an abnormal spinal curvature and hypotonia. Echocardiography revealed a small ostium secundum atrial septal defect. His developmental milestones were delayed: he sat alone at age of 9 months and walked unaided at 19 months. He was clumsy even in gross movement. The anterior fontanelle was open in infancy and closed at 24 months. He showed progressive kyphoscoliosis, which was managed with orthotic treatment for 4–5 months at age of 2 years and then surgery 3 times; however, the interventions were not beneficial. At age of 3 years, bilateral inguinal hernias were repaired. He also reported receiving bisphosphonates for osteoporosis. Growth hormone suppression test using oral glucose showed a nadir of growth hormone at 0.5 ng/mL and low IGF1 (post-load: 13.5 ng/mL; pre-load: 8.5 ng/mL; normal value: 26.8–134 ng/mL). We first met him at the age of 4 years (Fig. 1). He was very pleasant and understood the orders but responded to questions with simple words but without sentences. His voice was hoarse. His standing posture and gait were clumsy. Height was 138 cm, weight 40 kg, and OFC 57.7 cm (all above the 97th percentile). He showed macrocephaly and facial dysmorphism, including a sloped forehead, prominent supraorbital ridges, deep-set eyes, large and prominent nose, large ears, thin upper lip, pointed chin, and relatively small jaw. He looked more senile than his chronological age. The skin was soft and translucent but not of hyperextensibility or fragility. Pectus carinatum and mild cutis laxa of the lower abdomen with three small café-au-lait spots were seen. The hands were large, measuring 20.5 cm (>97th percentile), and feet were large as well. Flexion deformity of the large joints was noted, and mild contracture of the elbow and knee joints was evident. The testis was not palpable, and bilateral inguinal hernia was present. The neurological and ophthalmological examinations were normal. Concentrations of luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol, and estrone were all in the normal prepubertal range. His mother was 155 cm and father 170 cm tall.

Fig. 1.

Photographs of the patient at age of 4 years showing the dysmorphic facial features and the skeletal and joint abnormalities, and X-rays at age of 3 years showing a diffuse decrease in bone mineralization, abnormal appearance of the atlanto-occipital joint, severe scoliotic deformity of the thoracolumbar spine, and epiphyso-metaphyseal enlargement of the femur.

Full skeletal survey showed diffuse bone demineralization, hypertrophy of the sphenoid bone, leading to an abnormal appearance of the clivus and poorly identified sella turcica, an anomalous craniovertebral junction (atlanto-occipital impaction and unfused odontoid), cervical rib of the left side, severe thoracolumbar, poorly defined acetabular rim with rounded acetabular roof, coxa valga, enlargement of the metaphysis, and epiphysis of the long bones with otherwise preserved shape (Fig. 1). At 3.5 years old, the bone age of the patient was estimated to be 6 years according to Greulich and Pyle radiographic atlas of skeletal development. The excessive pre- and postnatal overgrowth occurring with the dysmorphic facial features, the hoarse voice, inguinal hernias, joint abnormalities, and distinctive skeletal features, such as metaphyseal widening and spondylar dysplasia, prompted the diagnosis of M-N-S syndrome.

Whole-exome sequencing (WES) revealed a heterozygous variant of unknown significance in IGF2 (NM_000612: c.412C>T, p.R138W), which was initially considered as a candidate because of previous reports on overexpression of IGF2 in Beckwith-Wiedemann syndrome [Murrell et al., 2004; Chao and D'Amore, 2008]. Nevertheless, segregation analysis excluded the hypothesis, as the paternally inherited variant is also carried by two unaffected siblings. A comparative genome hybridization analysis failed to detect any relevant chromosomal aberration. His genome-wide DNA methylation patterns were compared with those of 11 healthy controls, including the gender-matched healthy brother who is around 1 year older. CpG sites were filtered for those with 10% β methylation difference (difference >0.1 or lower than −0.1). Following Bonferroni correction, 476 differentially methylated sites were detected between the proband and controls (Fig. 2). None of these were in the genes related to known OGSs. Gene Ontology (GO) enrichment for these sites revealed enrichment for 11 GO terms with methyltransferase activity showing the most significant enrichment (online suppl. Table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000527215). GO enrichment analysis determines whether a particular set of genes is enriched for certain classes of gene functions classified as GO terms. This analysis revealed the differentially methylated gene PR/SET Domain 10 (PRDM10) to be related to methyltransferase activity as part of GO term 0008168 (Fig. 2b). We further examined DNA methylation EPIC probes overlapping the imprinting differentially methylated regions. A single significant CpG site in the GNAS differentially methylated region was hypomethylated in the patient (β methylation = 0.135; mean β methylation of controls = 0.246; β methylation of his healthy sibling = 0.249) (Fig. 2b). However, the approach used does not allow for correction for covariates including blood cell composition which is one of the limitations of this analysis.

Fig. 2.

a Volcano plot representing −log10 (adj. p value) against beta methylation difference when comparing DNA methylation in the patient versus controls. The significant differentially methylated sites following Bonferroni correction with a beta methylation difference >0.1 (10% methylation) in the patient are displayed in red (hypermethylated), whereas CpG sites with a beta methylation difference lower than −0.1 are highlighted in green (hypomethylated). b Boxplots showing beta methylation values for significant CpG sites in the methyltransferase gene PRDM10 and in the imprinted gene GNAS.

Discussion

Here is an additional report on M-N-S syndrome in a Lebanese boy presenting with congenital overgrowth, dysmorphic facial features, deformity of the large joints, inguinal hernias, osteoporosis, bone abnormalities, slightly low intellectual abilities, and decreased IGF1. We summarized his manifestations and those of previously reported affected individuals (Table 1). We ascertained that decreased bone density and mild intellectual disability were syndromic components. The former was previously reported in 2 patients [Sadeghi-Nejad and Karlin, 2005; Schmidt et al., 2007] and the latter in two as well [Nishimura et al., 2004; Schmidt et al., 2007].

Table 1.

Clinical features of the reported patients with M-N-S overgrowth syndrome

	Moreno et al., 1974	Nishimura et al., 2004	Sadeghi-Nejad and Karlin, 2005	Schmidt et al., 2007	Handa et al., 2017	Proband
Gestational age	Term	38 weeks	35 weeks	34 weeks	37 weeks	Term
Birth length and weight	60 cm/6,870 g	64.8 cm/6,100 g	61 cm/6,400 g	61 cm/6,600 g	54.5 cm/4,108 g	61 cm/5,600 g
Macrocephaly	+	+	+	+	+	+
Dysmorphic facial features	+	+	+	+	+	+
Prominent supraorbital ridges	+	+	+	+	+	+
Loose skin/hernia	ND/+	+/+	−/+	+/+	ND/+	+/+
Thoracic dysplasia	ND	+	+	+	+	+
Neonatal contractures of joints	+	ND	−	+	+	−
Lumbar kyphosis/platyspondyly	+/ND	+/+	+/ND	+/+	+/+	+/+
Widened metaphysis	+	+	+	+	+	+
Vertebral bodies abnormalities	+	+	+	+	+	+
Rhizomelia	ND/ND	+	−	+	−	−
Puberty	ND	Delayed	Normal	Precocious	Delayed	−
Hypothyroidism	ND	−	−	+	ND	−
Hypoglycemia/insulin hypersensitivity	ND/ND	ND/ND	−/–	+/+	ND/+	−/–
Low IGF-I/GH	ND/ND	+/–	−/–	+/+	+/ND	+/+
Decreased bone density	ND	ND	+	+	ND	+
Atrial septal defect	−	−	+	ND	ND	+
Difficulty to move	ND	+	+	+	ND
Hoarse voice	+	+	+	+	+	+
Intellectual disability	ND	−	−	+	−	+

ND, not determined. The table is reproduced and updated from Schmidt et al. [2007].

WES and comparative genome hybridization analyses did not reveal any causative variant or chromosome derangement, respectively, as with the case reported by Handa et al. [2017]. However, a DNA methylation analysis revealed 476 significant CpG sites, which have the most significant GO term enrichment for methyltransferase activities (online suppl. Table 1). Interestingly, methyltransferases have been widely linked to known OGS, including NSD1 involved in Sotos syndrome, EZH2 in Weaver syndrome, DNMT3A in an OGS with facial dysmorphism and intellectual disability [Tatton-Brown et al., 2014]. The probable methylation abnormalities may be a clue to the pathogenesis of M-N-S syndrome. The link between the M-N-S syndrome and methyltransferases needs to be further investigated and tested in a clinically homogeneous cohort of affected individuals. However, this is extremely challenging due to the rarity of this entity. Therefore, additional reports and methylation studies are required to reach the goal.

Statement of Ethics

Approval to conduct the study was obtained from the IRB of the Lebanese American University, Lebanon. Written informed consent for analysis and data and photo publication was obtained from the family in compliance with national ethics regulation.

Conflict of Interest Statement

Authors declare no conflicts of interests.

Funding Sources

This study did not receive any funding.

Author Contributions

Cybel Mehawej, Eliane Chouery, and Andre Megarbane designed the study, interpreted data, and wrote the manuscript. Nady El Hajj and Yosra Bejaoui performed the epigenetic studies. Valérie Delague performed WES. Maya Gerges contributed to technical work. Ghada Al Hage Chehade and Daniel Mahfoud contributed to the patient's clinical evaluation. All authors approved the manuscript.

Data Availability Statement

Data are available from the corresponding author upon request.

Supplementary Material

Supplementary data

Supplementary data

Funding Statement

This study did not receive any funding.