Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is a rare genetic disorder characterized by severe pre- and postnatal growth failure and microcephaly. We present two male siblings with MOPDII confirmed by the identification of compound heterozygous variants in the pericentrin (PCNT) gene. The first, a twin with intrauterine growth restriction, was diagnosed postnatally at four years of age after developing dysmorphic features and neurodevelopmental delays. His younger sibling was diagnosed prenatally via chorionic villus sampling. These cases highlight that MOPDII can result from compound heterozygous inheritance and underscore the importance of considering this diagnosis in severe, symmetric intrauterine growth restriction. A structured, multidisciplinary approach is essential for managing the complex comorbidities, including the high risk of cerebrovascular disease. Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities. The diagnosis of MOPDII is established in a proband with suggestive findings and biallelic loss-of-function pathogenic variants in PCNT identified by molecular genetic testing. Treatment of manifestations: Relies on symptomatic care from multidisciplinary specialists in pediatrics, orthopedics, dentistry, neurosurgery, cardiology, nephrology, endocrinology, and medical genetics, and from educators when learning difficulties are an issue. Surveillance: Routine follow up of growth and development as well as monitoring of any known or potential complications regarding hip or spine deformity, dental abnormalities, cerebrovascular disease, coronary artery disease, hypertension and/or kidney disease, diabetes mellitus, and/or educational issues. Agents/circumstances to avoid: Growth hormone supplementation in the absence of growth hormone deficiency; excessive nutritional supplementation in infancy. MOPDII is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PCNT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the PCNT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Small for gestational age (SGA) refers to the size of an infant at birth, and is defined as a birth weight and/or birth length below the -2.0 SDS for the gestational age. In approximately 10% of cases, SGA is not compensated for in the postnatal period, with the pathogenesis of this condition being attributed to various monogenic syndromes or chromosomal abnormalities. The difficulty in making a pathogenetic diagnosis in this group of patients is due, on the one hand, to the similarity of phenotypic manifestations in the structure of the disease, on the other hand, to the variability of clinical manifestations within a specific syndrome. Conducting various molecular genetic studies is the main method of diagnosing the form of SGA. Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is one of the most common genetic variants of SGA, with its phenotypic features including skeletal anomalies and cerebrovascular changes. The disease is caused by biallelic mutations in PCNT gene. This study presents the clinical characteristics of the first patient with microcephalic osteodysplastic primordial dwarfism type II in the Russian Federation. The nucleotide changes detected in the patient have not been previously described in the world literature. Задержка внутриутробного развития (ЗВУР) представляет собой патологическое состояние, характеризующееся низкой массой и/или длиной плода (≤-2 SD) для данного пола и гестационного возраста. Примерно в 10% случаев ЗВУР не компенсируется в постнатальном периоде, в основе патогенеза данного состояния в таком случае лежат различные моногенные синдромы или хромосомные аномалии. Сложность в постановке патогенетического диагноза в данной группе пациентов обусловлена, с одной стороны, схожестью фенотипических проявлений в структуре ЗВУР, с другой — вариабельностью клинических проявлений в рамках конкретного синдрома. Проведение различных молекулярно-генетических исследований является основным методом диагностики формы ЗВУР. Одним из наиболее распространенных наследственных вариантов задержки внутриутробного развития является микроцефальная остеодиспластическая примордиальная карликовость II типа (МОПК II типа), фенотипическими особенностями которой являются наличие скелетных аномалий и цереброваскулярных изменений. Заболевание обусловлено наличием биаллельных мутаций в гене PCNT. В данной работе представлена клиническая характеристика первого пациента с микроцефальной остеодиспластической примордиальной карликовостью II типа в Российской Федерации. Нуклеотидные изменения, выявленные у пациента, ранее не описаны в мировой литературе.

Skeletal dysplasias (SD) are rare genetic disorders affecting skeletal development and bone growth. Whereas specific gene mutations have been identified in many, however, the molecular signaling pathways contributing to the phenotype are poorly understood. The C-type natriuretic peptide (CNP) signaling pathway is a driver of normal endochondral bone growth and underlies the impact of several genetic disorders of bone growth, including achondroplasia, the most common form of SD. In this cross-sectional study of 73 children with SD, comprising 7 distinct forms, we have examined the association of plasma concentrations of bioactive CNP and bio-inactive NTproCNP (recognized bio markers driving growth) and of collagen X marker (CXM) (an established biomarker of the growth plate response) with age and with annualized height velocity (HV). Although significant associations were identified with age in several disorders, the association of NTproCNP and of CXM with HV was aberrant except in type II collagen disorders and MOPD II. In OI, CNP and NTproCNP were reduced in proportion to severity of OI phenotype. Reduction in CNP exceeded NTproCNP, suggesting that higher rate of clearance/degradation of bioactive CNP occurs in OI. Across a wide range of HV in subjects with OI, biomarkers were dissociated and unrelated to HV. Similar changes were observed in 3 other forms of SD (multiple epiphyseal dysplasia, microcephalic osteodysplastic primordial dwarfism type II, and Morquio A syndrome). Although limited numbers of affected individuals within each group were studied employing a single sample at one time point, the results indicate aberrant responses both within biomarkers and when related to HV. Importantly, we identify enhanced rates of CNP clearance in OI and other forms of SD, which suggests CNP agonists could have therapeutic benefits. Skeletal dysplasias (SD) are rare genetic disorders affecting bone development and growth. C-type natriuretic peptide (CNP) and collagen X marker (CXM) are proteins involved in bone growth and are impacted in SD. In this study of 73 children with SD, we have looked at these protein levels compared with age and height velocity (HV). In some of these conditions, there was an association between these levels and age. However, in all but 2 of these conditions, there was no association between these levels and HV, which is a change from the general population and indicates growth plate differences in this population.

A rare type of autosomal recessive skeletal disorder, known as microcephalic osteodysplastic primordial dwarfism (MOPD) type II, causes a wide range of clinical abnormalities, including skeletal dysplasia, microcephaly, abnormal skin pigmentation, insulin resistance, typical facial features, and severe tooth deformities. Given the diverse manifestations of MOPD disorders and the overlapping clinical characteristics among primordial dwarfism (PD) subtypes, mutation analysis is crucial for accurate diagnosis and confirmation of MOPD II. In this study, whole-exome sequencing (WES) and GAP-PCR were employed to identify relevant genetic variants in three patients suspected of having MOPD. The clinical characteristics of three Iranian patients exhibiting hallmark features of MOPD were assessed. All patients were the offspring of consanguineous marriages and were referred from various provinces of Iran. WES was performed, and the identified variants were prioritized according to the standard filtration criteria. In the next step, Sanger sequencing was conducted to validate the candidate variants identified through WES in patients and their parents. Finally, GAP-PCR was implemented to resolve conflicting results between WES and Sanger sequencing for one of the patients. Analysis of three distinct cases revealed a novel homozygous copy number variation (CNV) in Case 3, consisting of a 490 bp deletion harboring exon 19 in the PCNT gene. Additionally, a nonsense homozygous variant in the PCNT gene (c.2812 C > T, p.Gln 938*) was found in Cases 1 and 2. This pathogenic variant has been previously documented in the literature. Reporting a novel deletion in the PCNT gene improves genetic testing services, including PND and pre-implantation genetic diagnosis (PGD) for MOPD II.