Microcephalicosteodysplastic primordial dwarfism type 2 is a rare recessively inherited syndrome characterized by severe intrauterine growth restriction (IUGR), severe postnatal growth retardation, short stature, skeletal abnormalities and an unusually small head size and blood vessel abnormalities. MOPD 2 is caused by mutations in PCNT (21q22.3), encoding pericentrin, which anchors a wide range of centrosomal proteins and protein complexes during cell division. Disruption of pericentrin is thought to cause mitotic spindle defects, and impaired cell proliferation and contribute to the development of a wide variety of pathological conditions, including cancer and diabetes [1,2]. Affected individuals also tend to have a very small head size that is more than three standard deviations (SD) below the mean for a population termed microcephalic. The growth problems progress postnatally, causing stunted growth or short stature. In this report, we present the case of a 5year-old girl weighing 6.5 kg and complaining of short stature since birth. The growth problems associated with MOPD2 have their onset well before birth, with affected individuals demonstrating intrauterine growth restriction (IUGR). The growth abnormalities continue postnatally, with the final height in adulthood reaching no more than 20-40 inches. The diagnosis of this condition is complex, but most important is genetic testing involving the pericentrin gene. 

A 5 yearold girl first born of Non-consanguineous marriage came to paediatric OPD seeking treatment for severe growth restriction since infancy. There was no history of any systemic disease during gestational period, the mother’s pre-natal ultrasound showed symmetrical intrauterine growth restriction (IUGR) with oligohydramnios. He was delivered vaginally at 37 weeks 4 Daysof gestation with a birth weight of 1000 grams, length of 33 cm and head circumference of 30 cm. He was admitted to NICU because of his extreme low birth weight, despite of his weight he didn't need any ventilator support and discharged from the hospital at weight of 1700 grams. On detailed history regarding development, the child attained head holding at 4 months, sitting without support at 10m age, walking without 18m, Say Ma, Ba at 1.5 years and say two world sentences at 3.5 years and his teeth was erupted at 2 years of age.There was no family history of similar problem. Clinical examination showed a very thin girl, with squeaky voice; and small triangular head, pointed nose and narrow nasal bridge (Figure 1).The girl had small and dysplastic dentition (Figure 2) there was no other skeletal deformities.The rest of examination was normal including neurological exam. Her weight is6.5 kg, his height was 75cm and head circumference was 37cm. MRI Brain, total abdominal ultrasound and echocardiogram showed no abnormality. After ruling out other causes of growth restriction, whole exome sequencing test was recommended to determine genetic mutation may contribute to observed phenotype, the test identified a homozygous single base pair duplication in exon5 of PCNT gene (chr21:g.47766820dup T; Depth: 244x) that results in a frameshift and premature truncation of the protein 32 amino acids downstream to codon296 (p.Gin296ThrfsTer32; ENST00000359568.5) was detected. This mutation is a damaging mutation cause what known as microcephalic osteodysplastic primordial dwarfism type 2 

Microcephalic osteodysplastic primordial dwarfism is a syndrome characterized by the presence of intrauterine growth restriction, post-natal growth deficiency and microcephaly. The growth abnormalities continue postnatally, with the final height in adulthood reaching no more than 20-40 inches, a post-pubertal head circumference of 40cm or less, mild mental retardation, and bone dysplasia. The diagnosis of this condition is complex, and hence it is based mainly on a combination of a thorough medical history, physical examination, radiological tests, laboratory tests, and, most importantly, genetic testing involving the pericentrin gene. This condition can be confused with other forms of primordial dwarfisms and conditions with moderate to severe IUGR, such as Seckel syndrome, MOPD1, MOPD3, Russell-Silver syndrome, Antley-Bixler syndrome, Fanconi syndrome, and Meier-Gorlin syndrome. This condition is thought to be the result of a mutation in the PCNT gene encoding a protein called pericentrin, which anchors various centrosomal proteins and other protein complexes during mitosis, contributing to a wide variety of pathological manifestations due to abnormal cellular division. The PCNT gene with 47 coding exons is located on 21q22.3 and covers ~122 kb of genomic sequence. Moreover, variants in the PCNT gene, which codes the Pericentrin protein, can affect the cell cycle regulation and result in MOPD 2. Pericentrin protein is a part of amorphous pericentriolar material (PCM), which has 3,336 amino acids that binds to calmodulin and γ-tubulin in the centrosomes and interacts with protein Kinase A and cytoplasmic dynein required for the cell-cycle progression and spindle organization [3]. In our study identified a homozygous single base pair duplication in exon5 of PCNT gene (chr21:g.47766820dup T; Depth: 244x) that results in a frameshift and premature truncation of the protein 32 amino acids downstream to codon 296 (p.Gin296ThrfsTer32; ENST00000359568.5) was detected. Microcephaly and skeletal dysplasia are recognized as major hallmarks of MOPD II that have been reported in many cases with MOPD II including the present case [4-7]. Dental abnormalities like microdontia are also hallmark features of MOPD 2, which were identified in the present case. Due to the Kantaputra et al. study, PCNT dysfunction is associated with the permanent dental development, since it is involved in microtubule integrity and centrosome function [8]. In addition, some cases such as the cases reported by Ghosh et al. presented high-pitched voice, which were also seen in present case[9].Acanthosisnigricans is another clinical feature associated with MOPD 2, which was absent in present patient. As the disease is genetically homozygous, and examining the PCNT gene for the individuals with prenatal and postnatal growth abnormalities and microcephaly would help paediatricians and geneticists in diagnosing the disease. Furthermore, due to the lack of appropriate treatment for this disease, prenatal genetic diagnosis should be taken into consideration for the patients with similar phenotype.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Military Hospital Shimla, India. 

1. Willems, M., Geneviève D., Borck G., Baumann C., Baujat G., et al. "Molecular Analysis of Pericentrin Gene (PCNT) in a Series of 24 Seckel/Microcephalic Osteodysplastic Primordial Dwarfism Type 2 (MOPD 2) Families." Journal of Medical Genetics 47 (2010) pp. 797-802. DOI: https://doi.org/10.1136/jmg.2009.069360.

2. Hall, M. N., Raff M., and G. Thomas. Cell Growth: Control of Cell Size. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2004, pp. 167–192.

3. Zimmerman, W. C., Sillibourne J., Rosa J., and S. J. Doxsey. "Mitosis-Specific Anchoring of γ Tubulin Complexes by Pericentrin Controls Spindle Organization and Mitotic Entry." Molecular Biology of the Cell 15 (2004) pp. 3642-3657. DOI: https://doi.org/10.1091/mbc.e03-11-0796.

4. Abdel-Salam, G. M., Sayed I. S., Afifi H. H., Abdel-Ghafar S. F., Abouzaid M. R., Ismail S. I., et al. "Microcephalic Osteodysplastic Primordial Dwarfism Type 2: Additional Nine Patients with Implications on Phenotype and Genotype Correlation." American Journal of Medical Genetics Part A 182 (2020) pp. 1407-1420. DOI: https://doi.org/10.1002/ajmg.a.61585.

5. Ghosh, S., Garg M., Gupta S., Choudhary M., and M. Chandra. "Microcephalic Osteodysplastic Primordial Dwarfism Type 2: Case Report with Unique Oral Findings and a New Mutation in the Pericentrin Gene." Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 129 (2019) pp. e204–e211. DOI: https://doi.org/10.1016/j.oooo.2019.08.019.

6. Weiss, K., Ekhilevitch N., Cohen L., Bratman-Morag S., Bello R., Martinez A. F., et al. "Identification of a Novel PCNT Founder Pathogenic Variant in the Israeli Druze Population." European Journal of Medical Genetics 63 (2020) 103643. DOI: https://doi.org/10.1016/j.ejmg.2019.03.007.

7. Vakili, R., and S. Hashemian. "Primordial Dwarfism: A Case Series from North East of Iran and Literature Review." Journal of Pediatric Review 7 (2019) pp. 113-120. DOI: https://doi.org/10.32598/jpr.7.2.113.

8. Kantaputra, P., Tanpaiboon P., Porntaveetus T., Ohazama A., Sharpe P., Rauch A., et al. "The Smallest Teeth in the World Are Caused by Mutations in the PCNT Gene." American Journal of Medical Genetics Part A 155 (2011) pp. 1398-1403. DOI: https://doi.org/10.1002/ajmg.a.33984.

9. Ghosh, S., Garg M., Gupta S., Choudhary M., and M. Chandra. "Microcephalic Osteodysplastic Primordial Dwarfism Type 2: Case Report with Unique Oral Findings and a New Mutation in the Pericentrin Gene." Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 129 (2019) pp. e204–e211. DOI: https://doi.org/10.1016/j.oooo.2019.08.019.