Primordial dwarfism (PD) refers to a group of monogenic genetic disorders characterized by intrauterine growth restriction (IUGR) and severe, persistent postnatal growth retardation. These diseases have been associated with variants of multiple genes whose products are mainly involved in critical cellular biological processes such as maintenance of genomic stability, DNA damage repair, mRNA splicing regulation, and centrosome function. Variants of such genes can directly impair cell proliferation and developmental potential. With the widespread application of molecular genetic technologies such as high-throughput sequencing, significant progress has been made in the research of PD. This article focuses on the major subtypes of PD, including Seckel syndrome, Microcephalic osteodysplastic primordial dwarfism (MOPD) types I/III, MOPD type II, and Meier-Gorlin syndrome. It has systematically summarized the advances in their clinical phenotypic characteristics, pathogenic genes, and molecular mechanisms, with an aim to deepen the understanding of the essence of growth disorders associated with PD.

Background and Objectives.Primordial dwarfism (PD) is a rare group of genetic conditions where individuals experience severe growth restriction, both in the womb and after birth. From as early as the fetal stage, those affected are significantly smaller than their peers. What makes PD distinct is its slow but steady growth pattern, resulting in proportionate dwarfism, where all parts of the body are equally shortened. Diagnosing and managing PD presents significant challenges due to its rarity and the wide range of clinical and genetic variability. The main conditions in this group include Seckel syndrome, Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) types I/III, MOPD type II, Meier-Gorlin syndrome, and Silver-Russell syndrome (SRS). The first four-Seckel syndrome, MOPD types I/III, MOPD type II, and Meier-Gorlin syndrome-are associated with microcephaly, and together they are known as microcephalic PD. Given how uncommon PD is, establishing its exact incidence is difficult. It is estimated that about 4 million infants die within the first month of life, with 99% of these deaths occurring in the neonatal period. Materials and Methods. Accurately diagnosing PD requires meticulous evaluation, as it can be easily confused with other genetic disorders that also cause dwarfism. In this article, we present the case of a 10-year-old patient diagnosed with MOPD II, the most common and well-documented form of microcephalic PD. Results. Genetic analysis revealed a pathogenic variant in the PCNT (pericentrin) gene ((c.1550dup, p.Gln518Alafs*7), alongside a deletion of exons 37-41. Conclusions. This case sheds light on the clinical and genetic complexities of primordial dwarfism, underscoring the importance of timely and accurate diagnosis for effective patient care.

Primordial dwarfism (PD) is one of a highly heterogeneous group of disorders characterized by severe prenatal/postnatal growth restriction. Defects in various pathways such as DNA repair mechanism, impaired centrioles, abnormal IGF expression, and spliceosomal machinery may cause PD including Seckel syndrome, Silver-Russell syndrome. Microcephalic osteodysplastic primordial dwarfism (MOPD) types I/III, II, and Meier-Gorlin syndrome. In recent years with the wide application of exome sequencing (ES) in the field of PD, new genes involved in novel pathways causing new phenotypes have been identified. Pathogenic variants in CRIPT (MIM# 604594) encoding cysteine-rich PDZ domain-binding protein have recently been described in patients with PD with a unique phenotype. This phenotype is characterized by prenatal/postnatal growth restriction, facial dysmorphism, ocular abnormalities, and ectodermal findings such as skin lesions with hyper/hypopigmented patchy areas and hair abnormalities. To our knowledge, only three patients with homozygous or compound heterozygous variants in CRIPT have been reported so far. Here, we report on a male patient who presented with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant c.7_8delTG; p.(Cys3Argfs*4) was detected in CRIPT with the aid of ES. With this report, we further expand the mutational and clinical spectrum of this rare entity.

Primordial dwarfism is a group of genetic disorders which include Seckel Syndrome, Silver-Russell Syndrome, Microcephalic Osteodysplastic Primordial Dwarfism types I/III, II and Meier-Gorlin Syndrome. This genetic disorder group is characterized by intra-uterine growth retardation and post-natal growth abnormalities which occur as a result of disorganized molecular and genomic changes in embryonic stage and, thus, it represents a unique area to study growth and developmental abnormalities. Lot of research has been carried out on different aspects; however, a consolidated review that discusses an overall spectrum of this disorder is not accessible. Recent research in this area points toward important molecular and cellular mechanisms in human body that regulate the complexity of growth process. Studies have emerged that have clearly associated with a number of abnormal chromosomal, genetic and epigenetic alterations that can predispose an embryo to develop PD-associated developmental defects. Finding and associating such fundamental changes to its subtypes will help in re-examination of alleged functions at both cellular and developmental levels and thus reveal the intrinsic mechanism that leads to a balanced growth. Although such findings have unraveled a subtle understanding of growth process, we further require active research in terms of identification of reliable biomarkers for different subtypes as an immediate requirement for clinical utilization. It is hoped that further study will advance the understanding of basic mechanisms regulating growth relevant to human health. Therefore, this review has been written with an aim to present an overview of chromosomal, molecular and epigenetic modifications reported to be associated with different subtypes of this heterogenous disorder. Further, latest findings with respect to clinical and molecular genetics research have been summarized to aid the medical fraternity in their clinical utility, for diagnosing disorders where there are overlapping physical attributes and simultaneously inform about the latest developments in PD biology.