Microcephalic Dwarfism Research Articles

DONSON is required for CMG helicase assembly in the mammalian cell cycle.

DONSON is one of 13 genes mutated in a form of primordial microcephalic dwarfism known as Meier-Gorlin syndrome. The other 12 encode components of the CDC45-MCM-GINS helicase, around which the eukaryotic replisome forms, or are factors required for helicase assembly during DNA replication initiation. A role for DONSON in CDC45-MCM-GINS assembly was unanticipated, since DNA replication initiation can be reconstituted in vitro with purified proteins from budding yeast, which lacks DONSON. Using mouse embryonic stem cells as a model for the mammalian helicase, we show that DONSON binds directly but transiently to CDC45-MCM-GINS during S-phase and is essential for chromosome duplication. Rapid depletion of DONSON leads to the disappearance of the CDC45-MCM-GINS helicase from S-phase cells and our data indicate that DONSON is dispensable for loading of the MCM2-7 helicase core onto chromatin during G1-phase, but instead is essential for CDC45-MCM-GINS assembly during S-phase. These data identify DONSON as a missing link in our understanding of mammalian chromosome duplication and provide a molecular explanation for why mutations in human DONSON are associated with Meier-Gorlin syndrome.

PHGDH-related microcephalic dwarfism in two fetuses: Expanding the phenotypical spectrum of L-serine biosynthesis defect

Defects in L-serine biosynthesis are a group of autosomal recessive diseases resulting in a wide phenotypic spectrum ranging from viable to lethal presentations and caused by variants in the three genes encoding the L-serine biosynthesis enzymes, PHGDH, PSAT1, and PSPH. Neu-Laxova syndrome (NLS) is the fetal form of this group, characterized by multiple congenital anomalies including severe intrauterine growth retardation, cutaneous lesions extending from ichthyosis to severe restrictive dermopathy with ectropion and eclabion, edema, microcephaly, central nervous system abnormalities, and flexion contractures. Here we report on two unrelated fetuses with an attenuated phenotype of NLS, that initially evoked Taybi-Linder syndrome. They carry biallelic pathogenic variants in the PHGDH gene. These observations expand the phenotypic continuum of L-serine biosynthesis defects, and illustrate the phenotypic overlap between NLS and microcephalic primordial dwarfism.

In silico protein interaction screening uncovers DONSON's role in replication initiation.

CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.

Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size.

Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.

Seckel Syndrome: case report of functional motor recovery using proprioceptive neuromuscular facilitation/Kabat Method

Introduction: Seckel syndrome (SCKL) is a heterogeneous autosomal recessive disorder, the major characteristic of which is microcephalic osteodysplastic dwarfism, which is defined as severe intrauterine growth retardation, severe short stature, severe microcephaly, bird-like profile, retroverted chin and forehead, prominent nose, mental retardation and other congenital anomalies. Objective: Evaluate the therapeutic effect of proprioceptive neuromuscular facilitation/Kabat method (PNF/KM) for functional recovery in SCKL. Methods: A pre-treatment evaluation was performed, followed by an intervention involving PNF/KM. Sessions were held twice a week for ten weeks (total: 20 sessions), followed by a post-treatment evaluation. The evaluator and the therapist were blinded. The assessment instruments were Lawton & Brody's Activities of Daily Living (ADL) Scale, Disabilities of Arm, Shoulder and Hand (DASH), Short Physical Performance Battery, Timed Up and Go test and upper limb muscle strength using a digital dynamometer. Results: No significant changes were found regarding ADL Scale or DASH. However, functional gains were achieved in activities that require biomechanical and proprioceptive actions of the shoulder, arm and wrist. Regarding the Short Physical Performance Battery, improvement was found in variables that require stabilization, strength, balance and agility. An improvement was found in the execution speed of the Timed Up and Go test. An improvement in muscle strength was following the intervention. Conclusion: This study showed that the PNF/KM method was not able to improve the performance on activities of daily living, but improvements were found with regards to balance, stabilization, strength and agility of the upper limbs and lower limbs.

Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants

Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.

Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.

Simple SummaryThe use of next generation technologies has helped to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. Nonetheless, the sequencing of all protein-coding genes of an individual may lead to doubtful assignments of causality for non-pathological variants, so it is mandatory to perform comprehensive studies and screening of additional patients for new mutations. Here we describe a novel DNMT3A germline variant identified by whole-exome sequencing in a patient with multiple paragangliomas and papillary thyroid carcinoma. The increased methylation of DNMT3A target genes observed in the proband’s sample points towards a gain-of-function effect of the variant, contrasting with the inactivation caused by loss-of-function alterations commonly seen in other neoplasia and in patients with Tatton-Brown-Rahman syndrome. This finding stresses the diverse molecular outcomes and suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.

Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions

In brief: Gain-of-function mutations altering DNMT3A are identified as a new cause of microcephalic dwarfism. Modelling of the disease in mice show that the mutations abrogate DNMT3A binding to H3K36me2 and H3K36me3 and lead to aberrant DNA methylation of Polycomb-marked regions and therefore repression of growth genes.

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

Analysis of cilia dysfunction phenotypes in zebrafish embryos depleted of Origin recognition complex factors.

Meier-Gorlin syndrome (MGS) is a rare, congenital primordial microcephalic dwarfism disorder. MGS is caused by genetic variants of components of the origin recognition complex (ORC) consisting of ORC1-6 and the pre-replication complex, which together enable origin firing and hence genome replication. In addition, ORC1 has previously been shown to play a role in ciliogenesis. Here, we extend this work and investigate the function of ORC1 and two other members of the complex on cilia at an organismal level. Knockdown experiments in zebrafish confirmed the impact of ORC1 on cilia. ORC1-deficiency confers defects anticipated to arise from impaired cilia function such as formation of oedema, kidney cysts, curved bodies and left-right asymmetry defects. We found ORC1 furthermore required for cilium formation in zebrafish and demonstrate that ciliopathy phenotypes in ORC1-depleted zebrafish could not be rescued by reconstitution with ORC1 bearing a genetic variant previously identified in MGS patients. Loss-of-function of Orc4 and Orc6, respectively, conferred similar ciliopathy phenotypes and cilium shortening in zebrafish, suggesting that several, if not all, components of the ORC regulate ciliogenesis downstream to or in addition to their canonical function in replication initiation. This study presents the first in vivo evidence of an influence of the MGS genes of the ORC family on cilia, and consolidates the possibility that cilia dysfunction could contribute to the clinical manifestation of ORC-deficient MGS.

Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2/3 normally limits DNA methylation of polycomb-marked regions. Our findings implicate the interplay between DNA methylation and polycomb at key developmental regulators as a determinant of organism size in mammals.

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.

DNA replication gene implicated in microcephalic dwarfism

DNA replication gene implicated in microcephalic dwarfism

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects

Cellular homeostasis is maintained by the highly organized cooperation of intracellular trafficking systems, including COPI, COPII, and clathrin complexes. COPI is a coatomer protein complex responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. The importance of such intracellular transport mechanisms is underscored by the various disorders, including skeletal disorders such as cranio-lenticulo-sutural dysplasia and osteogenesis imperfect, caused by mutations in the COPII coatomer complex. In this article, we report a clinically recognizable craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, microcephalic dwarfism, and mild developmental delay due to loss-of-function heterozygous mutations in ARCN1, which encodes the coatomer subunit delta of COPI. ARCN1 mutant cell lines were revealed to have endoplasmic reticulum stress, suggesting the involvement of ER stress response in the pathogenesis of this disorder. Given that ARCN1 deficiency causes defective type I collagen transport, reduction of collagen secretion represents the likely mechanism underlying the skeletal phenotype that characterizes this condition. Our findings demonstrate the importance of COPI-mediated transport in human development, including skeletogenesis and brain growth.

Exploring microcephaly and human brain evolution

Microcephaly, a commonly documented finding in paediatric neurological practice, confers little diagnostic specificity. Defined by a significant decrease in head circumference, it does not do much to discriminate between the many processes that result in reduced cranial capacity. Given that reduced skull volume reflects the size of the underlying brain, microcephaly is either the consequence of impaired cerebral growth during development or destructive neurological insults. It may be the consequence of environmental, maternal, or genetic aetiologies that include birth asphyxia, intrauterine infections, teratogen exposure, metabolic disease, chromosomal abnormalities, and single gene disorders. Frequently, associated developmental anomalies or neurological findings assist to make specific diagnoses. However, microcephaly may occur in isolation, and when this is extreme (4 or more standard deviations below the population mean), a diagnosis of primary microcephaly (MCPH) is likely. Surprisingly, despite marked reduction in cerebral cortical volume, such patients have mild/moderate intellectual disability without additional neurological deficits. As an autosomal recessive genetic disorder, this condition has been extensively studied in recent years yielding significant insight into the cellular and regulatory mechanisms governing brain growth. Brain volume is reduced to as little as a third of normal in primary microcephaly. This is accompanied by simplified cortical gyration with an otherwise structurally normal brain on neuroimaging. Over the last 3 million years our brains have seen a three-fold increase in size1 and 100-fold increase in surface area through cortical folding (gyrification).2 Evolutionary parallels have consequently been drawn with the expectation that genes identified may provide insight into human brain evolution. Over the last decade seven genes have been identified:3MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ (CPAP), and STIL. All are expressed in the neuroepithelium during embryonic neurogenesis and localize to the centrosomes and mitotic spindle poles. It is therefore thought that primary microcephaly is a disorder of neurogenic mitosis,4 where impaired proliferation of neural progenitor cells results in reduced numbers of neurons and a smaller brain. By determining the orientation of the mitotic spindle, these centrosomal proteins may influence the mode of stem cell division, augmenting the stem cell pool and consequently, brain size. This could provide an explanation for how neurogenesis has been modified during primate evolution to achieve expansion of the cerebral cortex. Intriguingly, comparative genomic sequencing has detected adaptive sequence changes in some of the MCPH genes.5 This raises the possibility that changes in these genes have directly contributed to increasing brain size, though this conjecture remains to be proven. In the last 2 years, the phenotypes associated with the MCPH genes have been substantially extended. Firstly, exome sequencing has identified mutations in WDR62 in a range of severe brain malformations.6,7 These include phenotypes usually thought of as distinct diagnostic entities, such as pachygyria, lissencephaly, schizencephaly, polymicrogyria, and cerebellar hypoplasia. Furthermore, the association of mutations in WDR62 with asymmetric polymicrogyria, unilateral cerebrellar hypoplasia, or open-lipped schizencephaly, suggests that such lesions should not be automatically attributed to vascular-disruptive aetiologies. Secondly, MCPH genes have also been associated with microcephalic primordial dwarfism, a group of autosomal recessive disorders with global growth failure.8 Here, prenatal growth restriction is followed by a marked reduction in postnatal height as well as brain size. Mutations in both CEP152 and CENPJ have been reported9,10 but why mutations in the same genes should cause localized reduction in brain size or global growth failure remains unclear. Maintaining the centrosomal theme, pericentrin is also an established and major disease gene for microcephalic dwarfism. However, centrosomes are not the whole story; the recent identification of multiple genes encoding components of the DNA replication machinery11–13 and an RNA splicing gene14,15 have demonstrated that at least for microcephalic primordial dwarfism other mechanisms are in play. Lastly, progress been made on the most extreme microcephaly phenotype in which profound intellectual disability is accompanied by brain size a tenth of its normal weight. Mutations in the NDE1 gene have been reported by two groups.16,17 This gene encodes a centrosomal protein involved in neuronal migration, as well as mitotic spindle formation, these functions respectively explaining the observed partial deficiency in cortical lamination and extreme microcephaly with grossly simplified cortical gyral structure (microlissencephaly). As well as affording insight into neurobiology and evolution, the burgeoning list of disease genes will have diagnostic utility. Comprehensive molecular testing should soon be a realistic possibility, informing diagnosis and patient management as well as permitting families to make informed reproductive choices. Though screening these large genes with established sequencing technologies has been cumbersome, the advent of next-generation sequencing technologies in diagnostic laboratories will provide the realistic prospect of efficient and cost-effective testing to assist the clinician in dissecting the heterogeneous entity that is microcephaly.

Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome

Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.

Seckel syndrome with Morgagni hernia

Seckel syndrome is an autosomal recessive disease presenting with microcephalic dwarfism, mental retardation and facial and skeletal abnormalities. Morgagni hernia is quite rare, constituting 1-6% of all diaphragmatic hernias. It is asymptomatic, especially in childhood. Morgagni hernia has never been reported in patients with Seckel Syndrome. Here we report a 3-year-old boy diagnosed as having Seckel Syndrome with Morgagni hernia, which has to be considered during physical examination of patients.

Morphometric appraisal of the skull of Caroline Crachami, the Sicilian “dwarf” 1815?–1824: A contribution to the study of primordial microcephalic dwarfism

The skeleton of Caroline Crachami is a rare historical example of primordial microcephalic dwarfism (PMD). Studies show the condition to be heterogeneous, with at least three types, for which the assessment criteria rely on descriptive evaluations and/or simple measures with regard to cranial features. Advances in noninvasive imaging allow for a more complete morphometric examination of the skull of Caroline Crachami with the aim of clarifying aspects of the condition. In the present study, the skull of Caroline Crachami was three-dimensionally imaged with computed tomography (CT) and reconstructed in virtual space. Coordinates for a number of measurements were taken to represent interesting anatomies with an emphasis on those measures not easily replicated on the skull itself. Volumes of the endocranial cavity and sella turcica were also computed. These data were compared with normative values taken from the literature and measured from CT images of the Bosma collection. Findings indicate that the general size of the skull is equivalent to that of a 6- to 8-month-old, that the endocranial volume and cranial base angle are commensurate with that of a newborn, and that the sella volume is the same as that for an 8- to 15-month-old. Apart from these traits, the skull was well proportioned and within the range of normal variation for a skull aged between 2-9 years. We conclude that further quantitative analysis on related skulls is warranted in the study of PMD using the methods and techniques described.

The central nervous system in microcephalic primordial dwarfism: Is there a characteristic developmental brain pathology in Seckel or Seckel-like syndrome?

In spite of the description of more than 70 cases of Seckel syndrome (SS) or Seckel-like primordial microcephalic dwarfism, reports about investigations into the central nervous system pathology in SS remaind infrequent Here we comment on the thorough neuropathological examination of the brain in a familial case of Seckel-like microcephalic dwarfism. The male fetus of a 6 gravida, 3 para was aborted at 19 weeks of gestation after prenatal ultrasound examination with the demonstration of severe microcephaly and retarded intrauterine development The propositus had two healthy sisters. Of two aborted fetuses and one deceased sibling, the deceased had also exhibited a Seckel-like phenotype as well as, in MRI scans, micrencephaly, callosal agenesis and pachygyria. Neuropathological examination of the brain in the propositus resulted in the demonstration of two main categories of changes: (1) defective telencephalic midline structures (arhinencephaly as well as callosal, septal, fornical, and hippocampal agenesis), and (2) impairment of migration (micrencephaly with lack of cortical neuroblasts in both the telencephalon and the rhombencephalon as well as heterotopias in the former). These findings corresponded with those described in the few neuropathological and neuroradiological literature reports, indicating that there appears to be in SS-like primordial microcephalic dwarfism and a characteristic, although not specific brain pathology which might be adequately summarized by the designation mediodysgenetic micrencephaly. The genetic background of SS as a basis for the CNS maldevelopment is discussed.