1 Introduction

Short stature is a common condition affecting children due to genetic, epigenetic, and environmental factors. Advancements in genetic analysis have enabled the identification of new genetic causes, shedding light on the molecular mechanisms behind growth failure [1]. Mosaic variegated aneuploidy syndrome type 2(MVA2) is a rare autosomal recessive disorder characterized by chromosome gains and losses called constitutional aneuploidy in different chromosomes and tissues, especially trisomies, double trisomies, and monosomies [2]. MVA2 is due to defective cell division, causing disjunction of chromosomes during mitosis [3]. The clinical manifestations of MVA2 include intrauterine growth restriction, microcephaly, facial anomalies, and intellectual disability. Although mosaic aneuploidies should be observed on karyotype, they may be dismissed as an artifact. Only 15 cases with only 1 Indian family with MVA2 have been reported in the literature. We report another Indian family with two siblings with novel homozygous pathogenic variants in the CEP57 gene causing MVA2 (MIM#614114).

2 Clinical case report description

An Indian family engaged in third-degree consanguineous marriage brought their two affected children (referred to as F1 and F2) for evaluation of short stature. These were the first two girl siblings among the four children. Their parents were second cousins, and the family history (including the other two children) was unremarkable, as shown in Fig. 1 (Pedigree). They were enrolled in the study after taking written informed consent.

Fig. 1
figure 1

Family Pedigree. The proband (F1) and F2, 14 and 11 years, respectively, are affected. The rest of the family members are phenotypically normal

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The proband(F1), a 13-year-old Indian female, who her parents brought to the OPD with complaints of inability to gain height, is the first child, born via normal vaginal delivery at 37 weeks, with a birth weight of 1500 g (−2.14 SD) requiring neonatal intensive care unit admission for low birth weight. She had achieved milestones typically according to her parents but had poor academic performance with an intelligence quotient (IQ) of 70% and a mental age of 11 years, indicating mild intellectual disability. Growth retardation was observed after 5 years of age. On examination, her anthropometry revealed a height of 108 cm (− 6.27 SD), a weight of 16.5 kg (− 4.47 SD), and a head circumference of 49 cm (<− 3 SD). She had dysmorphisms like triangular face, telecanthus, low set ears, brachydactyly, clinodactyly, and overlapping 4th and 5th toe (Fig 2). Written consent was obtained to publish the images. Sexual maturity rating (SMR) showed pre-adolescent growth stage and cafe-au-lait spots over the vulva. The bone age was 14 years, and an abdominal ultrasound showed a small uterus with multiple small follicles in the ovaries. 2D Echo was normal. Brain MRI revealed a small pituitary gland.

Fig. 2
figure 2

Clinical photographs-frontal view showing triangular face (F1), Telecanthus (F2), overlapping fourth and third toe (F1), brachydactyly and fifth finger clinodactyly (F1)

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The younger sister (F2) of the proband was 11 years old. Her birth history was unremarkable. She exhibited microcephaly, facial dysmorphism, and low-set ears, consistent with her sister’s presentation. She had a history of recurrent respiratory infections. Her IQ revealed mild intellectual disability (68%) and a mental age of 8 years. On examination, her anthropometry revealed a height of 108 cm (<− 3SD), a weight of 15 kg (<− 3SD), and a head circumference of 47 cm (<− 3 SD). SMR showed pre-adolescent Stage. MRI of the Brain revealed a hypoplastic anterior pituitary similar to that of F1. The bone age was 10–12 years, and pelvic ultrasound showed normal findings. The mid-parental height was 158 cm. And the rest of the family members were healthy.

Short stature was evaluated as per the guidelines. Level 1 laboratory investigations like CBC, Liver and renal function tests, venous blood gas, and stool routine microscopy were all within normal limits for both affected siblings. Endocrinological evaluation for short stature revealed normal thyroid hormone levels, normal growth hormone, and cortisol levels. Karyotyping was performed in F1 and F2 by GTG Banding using a peripheral blood sample. 20 cells were analyzed, and five cells were karyotyped using ISCN-2020, revealing a normal female karyotype (46, XX). Although mosaic aneuploidies should be observed on karyotype, they were dismissed as an artifact in the report. Whole Exome Sequencing (WES) revealed autosomal recessive Mosaic Variegated Aneuploidy Syndrome Type 2 with homozygous CEP57 variant. WES revealed a c.1388_1391del (p.Lys463IlefsTer3) in exon 11 in the CEP57 gene (NM_014679.5) chromosome coordinates chr11:95831137-95831140 (GRCh38.p14)). This mutation could not be found in genomAD and ClinVar databases. Still, it is classified as likely pathogenic according to the guidelines recommended by the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was performed in the proband, affected sibling, and the typical sibling and confirmed the homozygous variant in the F1 and F2 (Fig 3).

Fig. 3
figure 3

Sanger sequencing of the variant in F1, F2, and unaffected sister showing the presence of the variant in CEP57 gene c.1388_1391del in homozygous state and unaffected sister being heterozygous for the same

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The proband was treated with Growth hormone in a local hospital for 1 year at the age of 13 years. The drug dose was 0.15–0.17  U kg−1 d−1. The patient was followed up after 20 months. Anthropometric examination revealed an insignificant change in height.

3 Discussion

Herein, we have discussed the clinical details of two Indian siblings with MVA2 and compared details of 15 more reported individuals (1 report each of Indian origin, Pakistani, Chinese and 2 Caucasian origin, 2 of Mexican, 4 of Moroccan ethnicity); a total of 17 patients with MVA2 [3,4,5,6,7,8,9,10,11,12] (Supplementary Table 1). We have discussed these patients’ phenotypic and molecular characteristics according to various ethnic backgrounds. According to our data, most of the molecular analyses reported homozygosity (15/17) given the autosomal recessive inheritance pattern, and 2/17 were compound heterozygous in inheritance. All reported variants were distributed in Exons 5,9,3,11, and Intron 3.

It is observed that individuals of Moroccan ethnicity are detected with a common variant, i.e., c.915_925dup, making it the most common variant detected so far in the literature.

Marked growth retardation is observed in all cases of prenatal origin 15/17(88%), which is a hallmark of this condition [4].

In 13/17 (76.5%) of these cases, various skeletal manifestations have been reported, including rhizomelic shortening of upper and lower extremities, brachydactyly, thumb hypoplasia, and osteolytic lesions in the skull [4]. Our siblings also had similar bony abnormalities. Research conducted by Aziz et al. on the mouse models mimicking the MVA Disease mutation found that the CEP57 protein regulates Fibroblast growth factor 2 (FGF2), a key molecule in bone formation. FGF2 has been shown to stimulate bone formation and is expressed in osteoblastic cells [7]. FGF2 has an established role as a binding partner of CEP57 involved in FGF2 nuclear translocation. This mechanism could explain the observed skeletal abnormalities in MVA2 individuals [4, 7]. Of the data available for facial dysmorphisms, nearly all patients 13/14 (92.8%) had dysmorphisms. Data was unavailable in 2 studies. Sparse hair was also seen in other cases, including our proband. However, the presence of microcephaly wasn’t a constant finding, seen in 10/17(58.8%) cases only [4]. Cognitive development was reported to be normal in 4(25%) cases, while both our cases had mild intellectual disability.

MRI brain was reported to be abnormal in 8/15(53.3%) cases. Individuals with missing data are not taken accountable. Our cases had pituitary atrophy in one sibling and hypoplasia in the other, which was similar to the other reported cases [6]. Additional phenotypic features in this report include the presence of a small uterus and multiple small follicles in the ovary on abdominal ultrasound and a cafe au lait spot over the vulva in our proband. It is important to note that these are just initial observations, and further studies are needed to confirm and expand upon these findings. However, incorporating these additional features into the discussion provides a more comprehensive understanding of the diverse phenotypic manifestations associated with MVA2.

Mosaic aneuploidies on chromosome metaphases are a universal hallmark of MVA syndrome. The karyotype was reported as normal in several cases like ours. Our patients had homozygous c.1388_1391del (p.Lys463IlefsTer3) mutation described first in the literature.

MVA2 is an ultra-rare single-gene disease with prenatal or post-natal onset growth failure with typical dysmorphic features of triangular face, relative macrocephaly, and short limbs. These two cases highlight the importance of genetic testing, especially in cases of short stature with no reported aneuploidies on karyotyping. Appropriate genetic testing is paramount in short-stature cases as it aids in accurate diagnosis, identification of specific genetic disorders, treatment, and decision-making, and facilitates familial and reproductive counseling.