Microcephalic Primordial Dwarfisms (Seckel Syndrome and MOPD)

Syndromic class of microcephalic primordial dwarfism: Seckel syndrome (ATR, ATRIP, RBBP8, CPAP/CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, NSMCE2, CEP295), microcephalic osteodysplastic primordial dwarfism type II (PCNT), the RNU4ATAC spectrum (MOPD I/III, Roifman and Lowry-Wood syndromes) and microcephalic dwarfisms due to defects of DNA replication and repair (DONSON, LIG4, XRCC4, WDHD1)

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

Sources for the table: [1–33]. Related entities: hereditary primary microcephaly (MCPH), the boundary of this class, Meier-Gorlin syndrome, Bloom syndrome and Fanconi anaemia.

1. Introduction

1.1. Founding description: from Seckel to Majewski

Primordial dwarfism refers to growth failure that begins in intrauterine life and persists after birth, so that the adult retains reduced proportions from the outset and not through acquired loss of growth [34]. When growth failure is accompanied by marked microcephaly, the term microcephalic primordial dwarfism (MPD) is used, a group of monogenic disorders in which head circumference (HC) and stature are, by operational definition, both below −4 standard deviations (SD) [11, 35].

Helmut Seckel, professor of paediatrics at the University of Chicago, published in 1960 the monograph Bird-Headed Dwarfs, in which he brought together 15 patients (13 from the literature and 2 of his own) with proportionate intrauterine and postnatal dwarfism, severe microcephaly, a "bird-headed" profile with receding forehead and chin, a large beak-like nose and severe intellectual disability (ID) [26, 36]. A later systematic review attributes the first description to Mann and Russell, in 1959 [37]. For two decades, the eponym was used for almost any child with microcephaly and short stature of prenatal onset, so that the literature before 2010 on "Seckel syndrome" mixes distinct entities and describes a natural history that does not take genetic heterogeneity into account [13, 36].

In 1982, Majewski and colleagues published three successive articles in the American Journal of Medical Genetics. The first proposed a delineation of Seckel syndrome [38]. The second described three unrelated patients with intrauterine growth restriction (IUGR) and almost identical bone changes, who differed from Seckel syndrome by disproportionate shortening of the forearms and legs in the first years, brachymesophalangy, brachymetacarpy of the first digit, "V"-shaped distal femoral metaphyses, triangular distal femoral epiphyses, a high and narrow pelvis, slipped capital femoral epiphysis and coxa vara, without growth hormone (GH) or somatomedin deficiency: osteodysplastic primordial dwarfism type II [39]. The third described an intrauterine dwarfism with platyspondyly and anomalies of the pelvis and clavicles, type III [40]. These publications showed that the most frequent form of microcephalic primordial dwarfism was not Seckel syndrome but MOPD type II (MOPDII) [36]. The "Sicilian fairy" Caroline Crachami, exhibited in the 19th century, probably had MOPDII [41].

Taybi and Linder had described in 1967 a congenital familial dwarfism with cephaloskeletal dysplasia [42]. Majewski and Spranger described in 1976 brachymelic primordial dwarfism, and Majewski's 1982 type I and type III were later recognised as expressions of a single entity, identical to Taybi-Linder syndrome, on the basis of patients with features of both types [13, 42, 43]. Roifman syndrome (1999: antibody deficiency, spondyloepiphyseal dysplasia, growth retardation and retinal dystrophy in 4 patients from 3 families) and Lowry-Wood syndrome (1975: two siblings with epiphyseal dysplasia, short stature, microcephaly and congenital nystagmus) were described as separate entities, before it was recognised that they share the genetic cause of MOPD I [44, 45].

1.2. Milestones of molecular discovery

The first molecular cause of Seckel syndrome was identified in 2003: a synonymous ATR variant that alters splicing, found in two consanguineous Pakistani families whose locus had been mapped to 3q22.1-q24 [46, 47]. In 2008, two groups simultaneously identified biallelic loss-of-function variants in PCNT: Rauch and colleagues called the disorder MOPDII, and Griffith and colleagues classified similar patients as Seckel syndrome with defective ATR-dependent signalling [48, 49]. In 2010, analysis of PCNT in 24 families showed variants in all 8 patients with a clinical diagnosis of MOPDII and in 5 of 16 with a clinical diagnosis of Seckel syndrome, and review of these 5 placed them in the MOPDII spectrum: the disorder is genetically homogeneous [50].

These were followed by CPAP/CENPJ (2010) and CEP152 (2010–2011), which cause both primary microcephaly and Seckel syndrome [51–53]; RBBP8 (CtIP), in the family that had defined the SCKL2 locus and in the family with Jawad syndrome [54, 55]; CEP63 [56]; ATRIP, the partner of ATR [57]; NIN [58]; DNA2 [34]; NSMCE2 [59]; and TRAIP [60]; in 2024, CEP295 was associated with Seckel syndrome 11 [2]. Before the genes were identified, exclusion of the first two loci in several families with Seckel syndrome and with MOPDII had already shown the clinical and genetic heterogeneity of the syndrome [61]. In 2011, two groups showed that MOPD I results from variants in RNU4ATAC, which encodes the U4atac small nuclear RNA of the minor spliceosome [62, 63]; the same gene was later associated with Roifman syndrome (2015) and Lowry-Wood syndrome (2018) [64, 65]. Extreme growth failure came to be recognised as a frequent presentation of ligase IV (LIG4) deficiency and XRCC4 deficiency, and DONSON emerged as a common cause of microcephalic dwarfism [66–68]. In 2026, biallelic variants in WDHD1, a structural component of the replisome, were described in 17 patients from 14 families [31].

1.3. Nomenclature and current classifications

The term "Seckel syndrome" has two definitions. In the original broad definition, it covers any microcephalic dwarfism with IUGR; in the narrow definition, it requires microcephaly more severe than the short stature, significant ID and a characteristic face with a sloping forehead [11]. The Oxford Desk Reference records the same ambiguity: in the original sense of "nanocephalic dwarfism" it encompassed all MOPDs, and today it mainly describes disproportionate microcephaly with moderate to severe ID and a beak-like nose [35]. Bober and Jackson avoid the eponym and use "microcephalic primordial dwarfism" for the group [26]. Online Mendelian Inheritance in Man (OMIM) maintains a phenotypic series PS210600 with eleven types: SCKL1 (ATR), SCKL2 (RBBP8), SCKL4 (CENPJ), SCKL5 (CEP152), SCKL6 (CEP63), SCKL7 (NIN), SCKL8 (DNA2), SCKL9 (TRAIP), SCKL10 (NSMCE2) and SCKL11 (CEP295); the relationships of CEP63 and NIN are listed as provisional, and the SCKL3 locus, linked to 14q in a 2003 study of Turkish families, was declared erroneous in an erratum, one of the families having a LIG4 variant [1, 2, 69, 70]. Smith's still mentions SCKL3 at 14q23-q24, which is outdated information [36]. The name "Seckel" does not cover PCNT in OMIM, although pericentrin was first described as a cause of "Seckel syndrome" [3, 49].

The 2019 Nosology of Genetic Skeletal Disorders included MOPD I, Roifman syndrome and Lowry-Wood syndrome in the group "primordial dwarfism and slender bones", and the 2023 revision calls MOPDII "PCNT-related MOPD", in the same group [11, 12, 71, 72]. The authors of the 2023 GeneReviews proposed the molecular term "RNU4atac-opathy" for the whole spectrum of biallelic RNU4ATAC variants, because the term does not presuppose a subset of features and requires a search for actionable manifestations, especially immunodeficiency, regardless of the clinical label that prompted testing [12]. In 2026, a cohort of 69 participants from 14 countries, integrated with 109 published cases, proposed a new classification based on the two main manifestations, microcephalic primordial dwarfism (MPD) and immunodeficiency (IMD), into four groups: MPD without immunodeficiency, MPD with immunodeficiency, immunodeficiency without MPD and other related disorders, with neither of the two [27]. Applied to the 65 liveborn patients of this cohort, the classification placed 11% in the MPD group, 20% in MPD-IMD, 54% in IMD and 15% in the "other" group; of the 17 patients with a clinical diagnosis of Taybi-Linder syndrome, 5 were placed in MPD and 8 in MPD-IMD, and of the 37 with Roifman syndrome, 33 were placed in IMD [27].

Orphanet groups these disorders in the clinical group "microcephalic primordial dwarfism" (ORPHA:324761), with entries for Seckel syndrome (ORPHA:808, which maps to eleven OMIM entries, one of which, 617523, corresponds in OMIM to a neurodevelopmental disorder with midbrain and hindbrain malformations due to ARHGEF2, and not to a form of Seckel syndrome), MOPD II (ORPHA:2637), MOPD I and III (ORPHA:2636, synonyms Taybi-Linder and Crachami type), the Dauber (NIN), Montreal, Toriello, Alazami and Walsh (ZNF335) types, and MPD syndrome with insulin resistance (ORPHA:436182, which groups NSMCE2 and XRCC4) [14–16, 19–21, 73–81]. Other forms with their own OMIM entry, such as microcephaly, short stature and polymicrogyria due to RTTN and microcephaly, short stature and impaired glucose metabolism due to PPP1R15B, lie at the boundary of the class [82, 83].

1.4. Entities included in this article and boundaries

This article covers the class of microcephalic primordial dwarfism in a uniform manner: Seckel syndrome in the molecular sense (SCKL1 to SCKL10 and ATRIP), MOPDII, RNU4atac-opathy and the microcephalic dwarfisms due to defects of DNA replication and repair that enter the first-line differential diagnosis (LIG4, XRCC4, DONSON, WDHD1). The boundary with hereditary primary microcephaly is continuous, because CPAP/CENPJ, CEP152, CEP63 and CEP135 cause both microcephaly with normal stature and Seckel phenotypes, and more than 52% of patients with primary microcephaly have short stature [13, 84]. Hereditary primary microcephaly, Meier-Gorlin syndrome, Bloom syndrome and Fanconi anaemia appear here only in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Common mechanism: few cells from the outset

The size of an organism depends mainly on the number of cells produced during development. The genes of microcephalic primordial dwarfism encode proteins of fundamental cellular processes: genome replication, the DNA damage response, messenger RNA splicing and centrosome function [85]. The withdrawn GeneReviews chapter on the primary microcephaly–Seckel spectrum distinguishes two mechanisms that add together [13]. The first is quantitative and global: a slower cell cycle reduces the total number of divisions, and compensatory mechanisms explain why growth failure is inconsistent and gene-dependent. The second is specific to the brain: brain volume depends on the number of neurons produced during neurogenesis, before 20 weeks of gestation, and the orientation of the mitotic spindle of each progenitor in the ventricular zone determines whether division is symmetric (two progenitors) or asymmetric (one progenitor and one neuroblast). Subtle changes in the dynamics of mitosis favour premature differentiation and deplete the progenitor pool, which explains why the brain is more affected than the body in the forms with disproportionate microcephaly.

The cellular processes involved include control of DNA integrity (double-strand breaks), entry into mitosis at checkpoints, the metaphase–anaphase checkpoint, centrosome duplication and the organisation and kinetics of the mitotic spindle [13]. The ATR kinase sits at the top of a damage signalling pathway similar to that of ATM, but activated by different lesions, mainly by single-stranded DNA exposed when replication encounters obstacles [13, 86]. Several gene products of the class, including pericentrin, CEP152, CtIP, DONSON and TRAIP, affect ATR-dependent signalling, which gives the class a common pathophysiological basis spanning centrosome, replication and damage response [49, 53, 55, 60, 68].

2.2. Table of the types in the class

Sources: [1, 2, 7–13, 22–25, 27, 28, 30, 31, 34, 47, 53, 55–60, 66–68, 87, 88].

2.3. PCNT and MOPD type II

PCNT (OMIM 605925) is located at 21q22.3 and encodes pericentrin [89], a coiled-coil protein of about 360–370 kDa with a C-terminal PACT domain that targets it to the centrosome, where it is present throughout the cell cycle [11, 26]. It is a main component of the pericentriolar material, anchors the γ-tubulin ring complex that initiates mitotic spindle assembly, acts with DISC1 in the formation of the microtubule network and prevents premature centrosome separation by inhibiting NEK2 [26, 30]. In its absence, spindles become disorganised and chromosomes segregate poorly [48]. Pericentrin also acts as a scaffold for signalling proteins, and cells lacking pericentrin have defective ATR-dependent checkpoint signalling; microcephalin and pericentrin regulate entry into mitosis through centrosome-associated Chk1 [11, 49, 90].

The mechanism is loss of function. Biallelic loss-of-function variants eliminate cellular pericentrin, the messenger RNA undergoes nonsense-mediated decay, and up to 2025 no single amino acid substitution had been described in patients with MOPDII [11, 91]. A partial exception is the single amino acid deletion NM_006031.6:c.9460_9462del p.(Lys3154del), pathogenic in a Thai family [92]. The variants are distributed along the 47 coding exons; in the original series, 29 null variants in 25 patients included 12 nonsense and 17 frameshift variants [91]. With only one pathogenic allele identified, the diagnosis is not excluded: there may be a cryptic variant on the other allele, demonstrated by functional studies showing absence of pericentrin [11].

Heterozygous missense variants of PCNT have been described in families with intracranial aneurysms with apparent autosomal dominant inheritance (published as p.R2728C and p.V2811L, = NM_006031.6:c.8182C>T p.(Arg2728Cys) and c.8431G>T p.(Val2811Leu), in exon 38, shared by affected members of two families, and five other missense variants in 164 patients with subarachnoid haemorrhage or aneurysm), and the Pcnt−/− mouse has vascular anomalies with intracranial haemorrhage [93]. GeneReviews considers that further study is needed to determine whether these variants are a risk factor; there is no other established allelic disorder [11].

2.4. ATR, ATRIP and RBBP8: the ATR signalling pathway

ATR (3q23) encodes a 2644-amino-acid kinase of the phosphatidylinositol 3-kinase-like kinase (PIKK) family, which also includes ATM, DNA-PK and mTOR [13]. When replication stalls, uncoupling between the polymerases and the MCM helicase exposes single-stranded DNA, which is coated by replication protein A (RPA); this recruits ATR through ATRIP. Once activated, ATR phosphorylates effectors such as CHEK1, BRCA1, MCM2, RAD17, RPA2, SMC1, TP53 and histone H2AX, coordinating replication, repair and cell cycle transitions; it also interacts with the FANCD2 complex [13]. Seckel syndrome 1 results from biallelic hypomorphic alleles that reduce ATR expression: the original variant, synonymous, activates two cryptic donor sites in exon 9 and leads to skipping of that exon and to a premature stop codon in exon 10 [13, 47]. ATR activation by ultraviolet (UV) radiation in non-replicating cells depends on nucleotide excision [47].

In 2012 the first patient with ATRIP deficiency was described, compound heterozygous for a nonsense variant producing a truncated protein unable to interact with ATR and an allele with aberrant splicing; ATRIP and ATR were reduced. In the same study, two unrelated British patients had the same compound heterozygous ATR variants, with greatly reduced expression [57].

RBBP8 (18q11.2) encodes CtIP, a nuclear endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in processing double-strand breaks and promotes the formation of single-stranded DNA, a cofactor for ATR activation, in the S and G2 phases [13, 55]. In the family that defined the SCKL2 locus, a splicing variant produces a truncated CtIP with a dominant-negative effect; in the family with Jawad syndrome, the variant is an exonic frameshift. SCKL2 cells have a low apoptotic threshold and hypersensitivity to damage, and overexpression of a comparable truncated CtIP in normal cells reproduces the cellular phenotype: a dominant-negative variant produces a recessively inherited disorder, because the effect only becomes clinically relevant in double dose [55]. The Jawad syndrome variant is a founder variant in Pakistan, shared by four families, with an estimated age of about 24 generations [30].

2.5. Centrosome genes: CPAP/CENPJ, CEP152, CEP63 and NIN

CPAP (encoded by CENPJ, current HGNC symbol CPAP) binds tubulin dimers and is required for centriole elongation; it forms a complex with SASS6 and CEP350 and is recruited to the centrosome, together with the PLK4 kinase, by CEP152 [13]. CEP152, the orthologue of fly Asterless, is a scaffold for procentriole formation, recruited by CEP63; the two form a ring around the proximal end of the parent centriole, which is disrupted in cells from patients with CEP63 variants [13, 56]. Cells from patients with CEP152 variants have fragmented centrosomes, monopolar and tripolar spindles, micronuclei and aneuploidies, and accumulate genomic defects due to replication stress with increased ATM activation and H2AX phosphorylation [13, 53]. Loss of CEP63 delays procentriole assembly and leads to monopolar and multipolar spindles and endopolyploidy; in the mouse, Cep63 deficiency causes p53-dependent microcephaly and infertility due to a defect in meiotic recombination, the latter not demonstrated in humans [13, 30]. Ninein participates in asymmetric cell division; its deficiency in zebrafish disturbs the anterior neuroectoderm and produces a small, square skull [58].

These genes show that primary microcephaly and Seckel syndrome are extremes of a spectrum: loss-of-function variants in CPAP/CENPJ and CEP152 have been described both in patients with normal stature and in patients with classic Seckel syndrome, and statures between −2 and −4 SD in patients with variants in RBBP8, CEP152, CPAP/CENPJ, CEP63 and PHC1 constitute an intermediate phenotype [13]. The designation MCPH4 was assigned to CEP152 between 2005 and 2012 and became MCPH9 when KNL1 was identified in the original MCPH4 family; publications from that period referring to MCPH4 concern CEP152 [13].

CPAP/CENPJ (13q12.12-q12.13) has 17 exons and encodes a 1338-amino-acid protein with five coiled-coil domains; the domain spanning residues 311 to 422 destabilises microtubules, and overexpression of the protein produces elongated centrioles, whereas its depletion prevents centriole amplification [94]. OMIM links the gene to two recessive phenotypes, primary microcephaly type 6 (MCPH6, 608393) and Seckel syndrome 4 (613676). The first MCPH6 variant, published as 17delC (p.Thr6fsTer3) and later as c.18delC (p.Ser7ProfsTer2), is normalised as NM_018451.5:c.18del, p.(Ser7LeufsTer4); it was found in the homozygous state in a Brazilian family and a Pakistani family, and later in 10 patients from three Pakistani families, which suggests a founder effect in that population [94, 95]; an Iranian family with the homozygous p.Thr821Met variant had, in addition to microcephaly, mild dysmorphism, seizures, joint stiffness and wheelchair dependence [94]. In Seckel syndrome 4, the variant in the last nucleotide of intron 11 in the Saudi family abolishes the consensus acceptor site and generates three transcripts; in 2022 a 32-year-old Italian woman with Seckel syndrome and the homozygous variant NM_018451.5:c.130A>T, p.(Lys44Ter), inherited from unaffected heterozygous parents, was described [94, 95]. The hypomorphic Cenpj tm/tm mouse reproduces much of Seckel syndrome: intrauterine and postnatal growth restriction, a flattened and sloping forehead, skeletal anomalies, loss of neurons by apoptosis (especially in the striatum), long-term memory deficit and delayed female puberty [94].

CEP152 (15q21.1) causes MCPH9 (614852) and Seckel syndrome 5 (613823), both recessive [96]. In MCPH9, three patients from eastern Canada had p.(Gln265Pro) in the homozygous state or in compound heterozygosity with NM_001194998.2:c.2959C>T p.(Arg987Ter); the truncated protein does not reach the centrosome [52, 96]. In Seckel syndrome 5, the splicing variant c.261+1G>C was found in the homozygous state in five consanguineous Turkish families with a common founder haplotype and in a French patient of Turkish origin, and was absent in 250 Turkish controls; it generates four aberrant transcripts, one of which (published consequence p.Val86_Asn87del) may retain some function [53, 96]. The remaining families of 2011 were compound heterozygous: a patient of Italian origin living in Germany (NM_001194998.2:c.2034T>G p.(Tyr678Ter) and c.2694+1G>T, with retention of intron 19) and a South African patient (2 bp deletion with frameshift in exon 27 and NM_001194998.2:c.2000A>G p.(Lys667Arg)) [96]. Rare CEP152 variants were enriched in a cohort of 81 patients with atrioventricular septal defect, an association that OMIM includes among those awaiting replication [96].

2.6. Genes of replication and replication stress tolerance

DONSON encodes a replisome component that stabilises replication forks; its loss causes severe damage through nucleolytic cleavage of stalled forks and compromises ATR signalling in response to replication stress [68]. WDHD1 encodes AND-1 (Ctf4), a scaffold essential for replisome assembly, fork stability and sister chromatid cohesion; hypomorphic variants cause aberrant splicing, a marked reduction in the protein, slower fork speed, spontaneous damage, a defect in the G1/S transition, micronuclei, multilobulated nuclei and premature chromatid separation [31]. TRAIP encodes an E3 ubiquitin ligase that moves to damage sites and is required for phosphorylation of H2AX and RPA2 in S phase after UV radiation and for fork progression through lesions [60]. DNA2 encodes a replication nuclease-helicase [30, 34]. NSMCE2 encodes the SUMO ligase subunit of the SMC5/6 complex; patient fibroblasts have micronuclei, nucleoplasmic bridges, slow recovery of DNA synthesis and fewer BLM helicase foci after fork stalling, changes corrected by the normal protein but not by a form lacking SUMO ligase activity, and silencing of the orthologue in zebrafish produces dwarfism [59].

2.7. Non-homologous end-joining genes: LIG4 and XRCC4

Double-strand breaks are repaired by non-homologous end joining (NHEJ), which directly joins the ends, or by homologous recombination, available in the S and G2 phases [86]. NHEJ is also required for V(D)J recombination of immunoglobulins and T-cell receptors. Its defects cause a spectrum ranging from radiosensitive severe combined immunodeficiency (SCID) to extreme growth failure: biallelic truncating variants in LIG4 are a frequent presentation of microcephalic primordial dwarfism, and variants in XRCC4, the obligate partner of ligase IV, reduce the protein and ligase activity and compromise the repair of radiation-induced breaks and the junctional diversification of immunoglobulins, but without clinical immunodeficiency or bone marrow failure [66, 67].

2.8. RNU4ATAC and the minor spliceosome

RNU4ATAC (2q14.2) has a single exon and encodes a non-coding RNA, U4atac, of the minor spliceosome, the complex that removes minor (U12-type) introns, present in about 700 human transcripts and with splicing and branch point sequences different from those of the major introns [12, 97]. U4atac, U11, U12 and U6atac exist only in the minor spliceosome, and U5 is shared; U4atac binds U6atac and loads it onto the complexes with U12, forming the catalytically active spliceosome [12]. Most pathogenic variants do not reduce the abundance of the RNA, but destabilise RNA–RNA or RNA–protein interactions; the mechanism is partial loss of function [12, 98]. Retention of minor introns varies between transcripts and tissues and is most pronounced in monocytes, with 25–40% retention in patients versus 2–4% in controls [12]. Introduction of normal U4atac into patient fibroblasts improves U12-dependent splicing, which confirms causality [62]. In 2026, RNA sequencing (RNA-seq) of 7 patients showed more than 40 times as many intron retention events in genes with a minor intron as in rare disease controls (median 282 versus 0), with no change in other splicing parameters [28].

The variants are concentrated in three functional regions of U4atac (NR_023343.3 numbering): the 5' stem II, which interacts with U6atac (n.1-19); the 5' stem-loop structure, which binds proteins during assembly (n.26-57); and the Sm protein-binding region at the 3' end, required for maturation (n.83-115) [12]. Biallelic variants in RNU6ATAC, another catalytic RNA of the minor spliceosome, cause early-onset autoimmune diabetes with immune dysregulation, with the same pattern of U12 intron retention [97].

A link between the splicing defect and immunodeficiency was proposed in 2026. In a Drosophila melanogaster model with a CRISPR/Cas9-induced homozygous mutation in stem II of U4atac (a region with 93% identity with the human sequence), which also reduced the amount of U4atac by altering the proximal promoter, growth retardation, neurodevelopmental defects, immunodeficiency, intestinal changes and early lethality appeared, rescuable by human U4atac [99]. The transcript of hopscotch, the only JAK homologue in the fly, retained a minor intron, with reduced protein and embryonic and larval haematopoietic defects corrected by expression of the normal transcript [99]. In peripheral blood mononuclear cells from patients with Roifman syndrome, full-length JAK1 was decreased, with lower molecular weight bands, JAK2 was unchanged and STAT5 phosphorylation after interleukin 2 stimulation was lower than in the carrier father and in a healthy donor, with 3 to 5 patients per assay [99]. The authors relate this hypofunction to the lymphopenia and hypogammaglobulinaemia, by analogy with biallelic STAT5B deficiency, which combines growth hormone insensitivity, immunodeficiency and autoimmunity [99]. The finding is preclinical, with ex vivo confirmation in a small number of patients, and does not demonstrate that the pathway explains the whole human phenotype. Two inferences of clinical interest follow from it, neither tested in patients: the response to somatropin in documented GH deficiency may be lower than expected, and pharmacological JAK inhibition, proposed as a hypothesis for the inflammatory manifestations, could worsen the immunodeficiency (§7.4 and §7.9).

2.9. Variant spectrum and normalisation

The following variants were normalised in VariantValidator against the MANE Select transcript (GRCh38) [95].

The synonymous ATR variant illustrates the limits of automated classification: the ClinVar record VCV000008307 (alias 2101A-G, OMIM 601215.0001) has an aggregate classification of "likely benign", based on a single 2021 submission with criteria, whereas the original study demonstrated the effect on splicing in patient cells [47, 104]. For RNU4ATAC, the n. numbering coincides between NR_023343.1 and NR_023343.3, but the coordinates of the first nucleotide differ by one base pair between Ensembl (ENST00000580972.1) and NCBI, and the MANE Select transcript was introduced only recently and is not yet implemented in many databases, which may cause annotation errors [28, 95]. In Roifman syndrome an 85 bp tandem duplication (nt. 16_100) has also been described, in nomenclature not conforming to current standards [12].

2.10. Genotype–phenotype correlations, penetrance and expressivity

In MOPDII there are no clinically useful genotype–phenotype correlations; there is variability between affected members of the same family, and heterozygous carriers are asymptomatic [11, 109]. In RNU4atac-opathy, homozygosity for NR_023343.3:n.51G>A (14 families) is associated with MOPD I at the severe end, homozygosity for n.55G>A (5 families) with a more moderate phenotype with longer survival, and homozygosity for n.16G>A, in stem II, with Roifman syndrome in two unrelated patients [12]. In the 2026 cohort of 60 patients, the 8 homozygotes for n.51G>A all had MOPD I, with a mean stature of −8.62 SD and HC of −10.2 SD (versus −5.2 and −6.8 SD in the overall cohort), and 4 of the 5 with survival data had died; all patients with shortened lifespan had genotypes consisting exclusively of n.50G>A, n.50G>C, n.51G>A or n.55G>A [28]. Another 2026 analysis confirmed that genotypes with both variants in the 5' stem-loop are associated with severe and lethal disease, and that a single variant outside this region is enough for a milder, later-onset phenotype dominated by immunodeficiency and immune dysregulation [110]. In the joint analysis of 176 patients (69 from the European cohort and 107 published), lethality, brain malformations, severe microcephaly and stature below −4 SD were associated with biallelic variants in the 5' stem-loop, and immunodeficiency, autoimmunity and inflammation with variants in stem II, regardless of the second allele, with exceptions in both directions; the 54 known pathogenic variants affect 28% of the gene's nucleotides, and none has an allele frequency of 1% in gnomAD, a sign of strong constraint [27]. Even so, n.13C>T (stem II) occurred both in Roifman syndrome and in MOPD I, no patient with Roifman syndrome had variants exclusively in stem II, and the less severe allele seems to determine the presentation; variability between siblings with the same genotype argues against individual predictions [12, 28]. In ligase IV deficiency, the position of truncating variants correlates with severity [66].

2.11. Allelic disorders and phenotypic expansion

Several genes of the class cause other disorders, sometimes with different inheritance. Heterozygous missense variants of ATR in the FAT domain, such as p.(Gln2144Arg), cause an autosomal dominant syndrome of cutaneous telangiectasias from infancy, patchy alopecia, mild anomalies of the hair, teeth and nails and susceptibility to oropharyngeal cancer, described in a lineage of 24 affected members over five generations; OMIM marks it as provisional, and a heterozygous ATR variant found on a tumour panel does not in itself confer a defined risk or indicate Seckel syndrome [30, 105]. DNA2 also causes progressive external ophthalmoplegia with mitochondrial DNA deletions of dominant inheritance (PEOA6) and a recessive Rothmund-Thomson-like syndrome (type 4), with poikiloderma, congenital cataracts and severe growth failure, described by a Brazilian group [111, 112]. DONSON causes microcephaly-micromelia syndrome, MISSLA and a type of Meier-Gorlin syndrome [68, 102, 103]. Variants in RNU4ATAC were found in 3 of 53 patients with Joubert syndrome without coding variants (5.6% of negative cases), with the molar tooth sign and skeletal involvement [113], and in 12 of 276 infants with early-onset diabetes [97].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts and what each one measures

The clinical data for this class come from small cohorts with different selection biases, and each figure should be read together with its population. For MOPDII, the reference cohort is the vascular substudy of the Primordial Dwarfism Registry (Nemours, United States): clinical records of 47 molecularly confirmed individuals, living and deceased, aged 3 to 41 years [11, 114]. The growth charts come from 26 patients with molecular or functional confirmation, the metabolic data from 21 patients, and the hip pathology data from 12 patients with complete records at one centre [115–117]. The classic series of Hall and colleagues (58 individuals, 2004) included patients now known to have other forms of MPD [26, 109]. For RNU4atac-opathy there are two 2026 cohorts, an international one with 60 patients (54 families, age from the prenatal period to 24 years, median 6 years) and a French and European one with 69 participants [27, 28]. For Seckel syndrome there are only series of a few families per gene; the review of 252 published cases with the clinical label of Seckel syndrome includes patients without a molecular diagnosis, some of whom have PCNT variants [25, 37].

3.2. MOPD type II

Growth and body composition

Growth restriction is recognisable on ultrasound between 12 and 14 weeks and worsens throughout pregnancy [26]. In the 26 patients of Bober's charts (mean gestational age at birth 34.8 weeks), birth length, corrected for gestational age, was −7.0 ± 2.4 SD (equivalent to the 50th percentile of a newborn of 28–29 weeks), weight −3.9 ± 1.1 SD (31–32 weeks) and HC −4.6 SD (30–31 weeks) [26, 115]. At skeletal maturity, mean stature was −10.3 ± 2.3 SD, weight −14.3 ± 7.7 SD and HC −8.5 ± 2.1 SD: the adult man has the stature of a boy aged 3 years and 10 months, the weight of a boy aged 5 years and 2 months and the HC of an infant of almost 5 months, and the adult woman has the stature of a girl aged 3 years and 11 months and the HC of a 6-month-old infant [26]. Mean adult stature is around 100 cm, and the brain is comparable in size to that of a 3-month-old infant [11, 48]. HC, relatively proportionate at birth, becomes a disproportionate microcephaly [109]. Growth velocity is slow but constant, with no pubertal growth spurt [115]. Infants and young children are thin, with little subcutaneous tissue; truncal obesity develops from 5–6 years and especially at puberty. The expected weight gain is about 2 g/day, from infancy to skeletal maturity [11, 26, 118]. GeneReviews and the review by Bober and Jackson give −8.5 SD for HC at birth; the abstract of the primary study of the charts gives −4.6 SD at term and −8.5 SD at maturity, the values adopted in this article [11, 115].

Face, voice and teeth

The nose is prominent, with a broad bridge and root, a full tip and the columella below the alae nasi; this appearance is not evident in the newborn and becomes characteristic during the first year [26]. The ears are simple or mildly dysplastic, with attached or absent lobes, small for age but proportionate to the head; micrognathia is mild to moderate; the eyes appear prominent in childhood and less so with age; the palpebral fissures may be downslanting; the forehead is not sloping [26, 36]. The voice is high-pitched and nasal [11, 36]. The primary teeth are small for age, widely spaced, with deficient enamel and sometimes hypodontia. The permanent teeth are absolutely and relatively small, dysplastic, with enamel hypoplasia and absent, short or single roots in the molars; chewing is compromised, and in the second and third decades many teeth fall out or are extracted and replaced by dentures or implants [11, 26]. In a Thai family, the mandibular incisors and premolars measured about 2–2.5 mm mesiodistally, and hypoplastic alveolar bone led to the loss of most of the permanent teeth [92].

Skeleton

Skeletal dysplasia is present in virtually all patients, but may be difficult to recognise in the newborn [11]. At birth, the pelvis is high and narrow, with small iliac wings and flat acetabular roofs. Over time, slender long bones appear with progressive metaphyseal widening, delayed epiphyseal ossification, triangular distal femoral epiphyses and inverted "V"-shaped distal femoral metaphyses, mesomelia more marked in the upper limbs, distal shortening of the ulna with bowing of the radius, dislocation or subluxation of the radial heads with limited elbow movement, brachymesophalangy, brachymetacarpy of the first and fifth digits, metacarpal pseudoepiphyses, cone-shaped and ivory phalangeal epiphyses and clinodactyly of the fifth finger; bone age is always delayed and disharmonic [11, 26, 41]. The patellae are present and proportionate [26]. Fractures are not more frequent and heal normally [26].

In the series of Karatas and colleagues, 8 of 12 patients and 13 of 24 hips (54%) had pathology: coxa vara in 4 patients (3 unilateral and 1 bilateral), dysplasia with bilateral subluxation, coxa valga with subluxation and osteoarthritis, developmental dislocation and bilateral avascular necrosis diagnosed at 12 years [26, 117]. The small, hypoplastic proximal femoral epiphysis appears to slip along the shaft; coxa vara begins between 2 and 5 years and becomes severe within 6 to 10 months [26]. Scoliosis, especially in girls in late childhood or at puberty, may progress rapidly; GeneReviews shows a 110° thoracolumbar curve at 13 years [11, 26].

Global vascular disease

Vascular disease is the main cause of morbidity and mortality in MOPDII. In the cohort of 47 patients, 64% had moyamoya, intracranial aneurysms or both: 25 with aneurysms (many with more than one), 22 with moyamoya, 17 with both and 17 with neither; about half of the patients with neurovascular disease had a stroke, ischaemic or haemorrhagic [11, 114]. The risk of moyamoya is greatest before 5 years and begins in utero, with prenatal ischaemic strokes described; the risk of aneurysm persists throughout life [11, 26]. Stenosis begins in the supraclinoid internal carotid artery or in the A1 or M1 segments, first on one side and then bilaterally, progressing to occlusion with collateral circulation; one child progressed from almost undetectable stenosis to complete occlusion in 2 years [26, 119]. Aneurysms appear to result from prolonged haemodynamic stress on abnormal vessels [26]. The review of 147 published cases found cerebrovascular disease in 32%, with occlusive disease at younger ages and with rapid and silent progression, and cerebrovascular disease caused the death of 23% of the patients with CNS vascular disease described [26, 120]. A systematic review of intracranial aneurysms in MPD brought together 24 patients with 71 aneurysms (median 3 mm), 50% with subarachnoid haemorrhage, a mean age of 16.2 years, concomitant moyamoya in 37.5% and overall mortality of 45.8% [121]. Acute cognitive decline may be the presentation of moyamoya [26, 119].

The vasculopathy extends beyond the brain. In the cohort of 47 patients, 43% had hypertension (median age 13 years), more than 32% hypercholesterolaemia (median 18 years) and 17% acute myocardial infarction (AMI): 8 patients with AMI between 17 and 33 years (mean 24 ± 5.2), some with more than one event [11, 114]. The external carotid, renal and coronary arteries may be affected, and at least 6 patients had femoral artery occlusion after catheterisation [11]. Bober and Jackson describe a 17-year-old boy with stenosis of the left anterior descending and first diagonal arteries treated with angioplasty and two stents, who needed coronary bypass surgery 5 years later and died of AMI about 18 months afterwards, and a 23-year-old woman treated with stents in the circumflex and right coronary arteries [26]. Congenital heart defects (atrial septal defect, ventricular septal defect, patent foramen ovale) occur in about 25–28% [11].

Kidney, metabolism and endocrinology

One-third of the cohort of 47 patients had chronic kidney disease (CKD), of unspecified cause, with stage III diagnosed at a mean age of 22 years; two patients received a kidney transplant at 21 and 23 years, one with a renal artery aneurysm; six had nephrolithiasis in early adulthood, all on antihypertensive drugs; accessory or duplicated renal arteries were found in 7 men and in no women [11]. Hypertension may be renovascular or of central origin; all hypertensive patients described in the literature up to 2017 had moyamoya, and in one of them cerebral revascularisation reduced systemic blood pressure; many have proteinuria [26].

In the series of 21 patients with PCNT variants, 18 had insulin resistance, severe in most, 10 had diabetes (mean age at onset 15 years, range 5 to 28) and 13 metabolic dyslipidaemia; all patients without resistance were under 4 years of age, and resistance appears mainly between 5 and 10 years [26, 116]. In at least 3 patients, insulin resistance was detected during GH treatment [26]. Pericentrin is highly expressed in skeletal muscle, and its silencing in adipocytes halves insulin-stimulated glucose uptake, in parallel with a defect of proliferation and adipogenesis, without altering proximal insulin signalling [116]. Acanthosis nigricans, which darkens with sun exposure and with GH, and hepatic steatosis accompany insulin resistance [11, 26]. Sexual maturation is typical and menstruation normal, but puberty was precocious in 6 of 21 girls over 8 years, and one case of polycystic ovaries has been described; both may result from insulin resistance [26]. Smith's also mentions premature ovarian insufficiency [36]. Up to 2017 no pregnancies in women or paternity in men with MOPDII had been documented [26].

Neurodevelopment and behaviour

Despite the extreme microcephaly, intellectual development is generally in the typical to borderline range, social skills are good and the personality is outgoing; many children are hyperactive and distractible [11, 109]. Patients attend mainstream schools and some have gone to university, but independent living is difficult in adulthood [11]. Moderate to severe ID has been observed only after stroke [26]. Bone Dysplasias describes "mild to moderate mental deficit in most", a finding that reflects older series with mixed diagnoses [41]. Neuroimaging may show a simplified gyral pattern and hypoplasia of the corpus callosum [11, 122].

Skin, blood and other findings

Ovoid café-au-lait macules, with smooth borders and up to 2 cm, become more evident with age; there is cutis marmorata in infancy, multiple creases on the hands and feet ("wrinkled hands"), hypopigmentation and dry skin later on, fine and sparse hair and thin eyebrows [11, 26]. Asymptomatic thrombocytosis and anaemia occur in more than 75%, and leucocytosis is frequent; in a Turkish series of 8 patients, 87.5% had thrombocytosis and 75% leucocytosis [11, 123]. Mild iron-deficiency anaemia appears after menarche [26]. Subglottic stenosis (with tracheostomy in at least two patients), occasional craniosynostosis, hypermetropia, sensorineural hearing loss, glaucoma, inguinal hernia, cryptorchidism or retractile testes (44% of males) and hypospadias (8%) complete the picture [11, 36, 109].

Life expectancy

Life expectancy is reduced by the comorbidities, which, untreated, lead to death mainly in early adulthood, over a range of 7 to 41 years [11]. In 2017, the oldest molecularly confirmed patient known to the authors was 39 years old [26].

3.3. Seckel syndrome

Overall clinical picture

In the classic definition, Seckel syndrome combines moderate prenatal growth deficiency with severe microcephaly, postnatal growth deficiency and progressive disproportionate microcephaly, without skeletal dysplasia or body disproportion [36]. Mean birth weight in historical series was about 1500 g (1000–2000 g); mean HC in children and adults is about −9 SD, more severe than stature in half of the patients; mean postnatal stature is around −7 SD, with values down to −13 SD [13]. Smith's illustrates a newborn girl of 38 weeks weighing 1651 g, measuring 41 cm and with an HC of 28 cm, whose body proportions and adiposity were almost normal [36]. ID is usually moderate to severe (intelligence quotient below 50 in half of the patients), with hyperactivity, aggressive behaviour and seizures [13, 36]. The "bird-headed" face results from relative preservation of the midface: a narrow, sloping forehead, proportionately prominent eyes, upslanting or downslanting palpebral fissures, a large convex nose, a receding mandible, small teeth and small pinnae that are proportionate to the head, often without a lobe [13, 36]. Imaging shows gyral simplification, sometimes atrophy, and radiographs show markedly delayed bone maturation and cone-shaped or ivory epiphyses [13, 36]. Occasional anomalies include craniosynostosis, iris coloboma, ptosis, pectus carinatum, camptodactyly, syndactyly, polydactyly, clinodactyly, hallux valgus, café-au-lait macules, heart disease and anomalies of the epiglottis [36]. The 2013 review counted fewer than 50 convincing cases published before 2010, and in 2023 there were about 40 molecularly confirmed patients in nine genes [13, 25].

Differences between genes

The ATR and ATRIP forms have extremely severe microcephaly and growth retardation (HC of −12 SD and stature of −5 SD in the original family), microtia, micrognathia and dental crowding; some patients have skeletal changes, including small patellae, a feature shared with Meier-Gorlin syndrome [47, 57]. CEP63-related Seckel syndrome has mild to moderate ID, and in the second family described only one of three siblings had severe short stature; two had aggressive behaviour [25]. The NIN form was described in two sisters with severe ID [58]. In the TRAIP form, the three original children had extreme disproportionate microcephaly, a reduced cortex with simplified gyri, a narrow and elongated face and micrognathia; recurrent lower respiratory tract infections were the main morbidity, and one child died at 10 years of respiratory failure due to chronic lung disease; one had persistent lymphopenia without a demonstrated adaptive immune defect [30, 60]. The NSMCE2 form is distinguished by its metabolic component: extreme insulin resistance with hypertriglyceridaemia and hepatic steatosis, primary gonadal failure, renal lithiasis, platyspondyly, bifrontal gyral simplification, a cavernous carotid aneurysm and, in an 11-year-old boy described in 2026, bilateral developmental maculopathy [59, 87]. Two Jewish siblings of Indian origin with a homozygous tandem duplication in NSMCE2 had severe postnatal growth restriction, hypothyroidism, late-onset insulin-dependent diabetes, borderline immune dysregulation and recurrent pneumonia with interstitial lung disease that led to their death in adolescence; their cells had spontaneous chromosome breaks and polyploidy, without hypersensitivity to cross-linking agents [88]. Seckel syndrome 11 (CEP295), described in 2024 in a Chinese boy and in three Hispanic siblings, combines severe primary microcephaly, short stature, global delay, mild ID, facial dysmorphism, digital anomalies and pachygyria [2]. The Jawad family (RBBP8) had primary microcephaly, short stature, tetramelic polydactyly, syndactyly of the 2nd and 3rd digits and complete absence of nails [13].

Blood, neoplasms and vessels

Smith's states that haematological disorders may occur and that some data suggest greater sensitivity to chemotherapy [36]. Some patients with Seckel syndrome without molecular confirmation developed myelodysplasia; a woman measuring 113 cm and weighing 14.8 kg at 26 years had acute myeloid leukaemia at that age, and chemotherapy caused severe toxicity with profound bone marrow aplasia and death two months later [1, 124]. As early as 1987 a subgroup with chromosomal instability and/or haematological changes had been proposed, although two Arab patients studied had no Fanconi-type defect [1]; the haematological risk has not been systematically assessed or linked to a genotype [13, 124]. In patients with TRAIP, no cancer predisposition was observed, although all were children at the time of description [30]. In the review of 253 cases with the clinical label of Seckel syndrome, 27.7% had CNS anomalies and 3.16% (8 patients) CNS vasculopathy, with moyamoya in 1.97%; the mean age was 13.25 years, the aneurysms mainly affected the posterior circulation, and 3 of the 8 died [37]. These authors' index case had a PCNT variant, and the article itself notes that patients with PCNT variants labelled as Seckel syndrome have more severe growth restriction; the vasculopathy attributed to "Seckel syndrome" may in part correspond to unrecognised MOPDII [26, 37]. Bober and Jackson consider cerebrovascular disease exclusive to MOPDII among the forms of MPD, but NSMCE2 syndrome included a cavernous carotid aneurysm [26, 87]. Dilated cardiomyopathy and multiple ventricular septal defects have also been described in patients with a clinical diagnosis of Seckel syndrome [125], as has a fatal AMI in a 30-year-old man weighing 11.5 kg with a previously embolised intracranial aneurysm, whose molecular diagnosis is not mentioned in the abstract of the report [126].

3.4. RNU4atac-opathy

Spectrum

All patients have growth restriction, microcephaly, skeletal dysplasia and cognitive deficit, of variable severity; less constant are brain anomalies, seizures, stroke, immunodeficiency, heart disease and ophthalmic, cutaneous, renal, gastrointestinal, auditory and endocrine involvement [12].

Source: [12], Table 3.

MOPD I (Taybi-Linder syndrome)

This is the most severe form and accounts for about two-thirds of published patients [27]. Growth restriction is extreme, with brachymelic proportions; carriers of n.55G>A are taller, about −4 SD [12, 36]. The skull is microcephalic and dolichocephalic at birth, later brachycephalic, with a prominent occiput, sloping forehead, ridged metopic suture and fontanelles that close early; the eyes are prominent, the nasal root high and broad, the nasal tip bulbous with age, the lips full, the chin small, the ears small, low-set and rotated, the hair and eyebrows sparse and the skin dry and sometimes hyperkeratotic [12, 36, 42]. The skeleton shows platyspondyly, cleft vertebral arches, relatively long clavicles, short and broad ilia with horizontal acetabular roofs, short, bowed tubular bones without metaphyseal widening, markedly delayed ossification, dislocation of the hips and elbows and, sometimes, osteopenia with fractures and patellar hypoplasia [12, 36, 42]. Brain malformations include lissencephaly, pachygyria, heterotopias, agenesis of the corpus callosum, colpocephaly, interhemispheric cyst, agenesis or hypoplasia of the vermis and arachnoid cyst; some patients required shunting for hydrocephalus or drainage of cysts [12, 36]. The delay is profound: some children sit, but most do not stand, walk or speak, and families describe them as "eternal infants" [12]. Seizures are frequent, and infants have recurrent apnoeas [12, 42].

Strokes, described up to 2023 only in MOPD I, occur in the setting of physiological stress (severe illness, fever, anaesthesia): autopsies of young children showed acute and chronic infarcts mainly in the brainstem, but also in the cerebral lobes, white matter and deep nuclei, without a vascular distribution and with normal vascular anatomy [12]. Other findings in MOPD I are persistent neonatal hyperbilirubinaemia with or without hepatosplenomegaly, congenital anomalies of the kidney and urinary tract (CAKUT) with cystic or dysplastic kidneys, tubulopathy in infancy, cryptorchidism with micropenis and preaxial polydactyly with hypoplastic thumbs [12, 36]. Historically, most died before 28 months, often before 1 year and mainly from infections; GeneReviews notes that many of these children probably had unrecognised immunodeficiency and that some live for several years, with an 18-year-old man homozygous for n.55G>A described [12, 35, 36, 42, 127].

Roifman and Lowry-Wood syndromes and attenuated phenotypes

Roifman syndrome combines antibody deficiency with recurrent infections, spondyloepiphyseal dysplasia, growth retardation, retinal dystrophy and mild ID; the upper lip is thin, the philtrum long and the nasal tip narrow [12, 44]. Neonatal cholestasis, hepatosplenomegaly, hepatic fibrosis with extramedullary haematopoiesis, tubulopathy in late childhood, hypogonadotrophic hypogonadism and, in one patient, non-compaction cardiomyopathy with heart failure at 14 years have been described [12]. Lowry-Wood syndrome has multiple epiphyseal dysplasia, stature of −3.5 to −6.3 SD, HC of −5 to −9 SD, nystagmus and mild to moderate ID; puberty was normal in at least one man and one woman [12, 45, 65]. In these forms the children speak and walk, but formal assessment may reveal a greater cognitive deficit than perceived [12]. The degree of cognitive deficit does not correlate with the degree of microcephaly, and absence of microcephaly does not exclude the diagnosis [12].

The diagnosis of Roifman syndrome may come in adulthood. In a British man, hypogammaglobulinaemia was attributed for years to sodium valproate; he had asthma, recurrent otitis, epilepsy, mild learning difficulties, mild bronchiectasis, chronic kidney disease with small kidneys, intermittent thrombocytopenia and terminal ileal inflammation [107]. IgG fell from 7.8 g/L (2008) to 2.91 g/L (2020), with no response to pneumococcal vaccine, and withdrawal of valproate restored IgM, but not IgG or IgA [107]. At 45 years a non-ischaemic dilated cardiomyopathy appeared, with mid-wall septal fibrosis on MRI and normal coronary arteries, and genome sequencing identified NR_023343.1:n.[13C>T];[13C>G] in RNU4ATAC [107]. Stature was 157.5 cm, without microcephaly, without confirmed skeletal dysplasia and without retinal dystrophy; there was brachydactyly, subtle clinodactyly of the fifth finger and a thin upper lip, and the B lymphocytes were mainly non-class-switched memory cells [107]. Immunoglobulin replacement, started in 2020, reduced infections and respiratory exacerbations, and the dose was later reduced while maintaining an IgG trough above 8 g/L [107]. Together with the non-compaction cardiomyopathy described at 14 years, the case places Roifman syndrome in the differential diagnosis of non-ischaemic cardiomyopathy in a young adult with antibody deficiency, even without the skeletal, retinal and growth triad [12, 107].

The retinal dystrophy has the profile of a cone-rod dystrophy: reduced central acuity, constricted visual fields, poor dark adaptation, pale discs, narrowed vessels and pigmentary changes, with variable nystagmus; strabismus and dense congenital or early-onset cataracts have also been described [12]. Immunodeficiency is present from infancy, with hypogammaglobulinaemia, deficient antibody response and B and/or T lymphopenia, and the frequency and severity of infections improved with immunoglobulin replacement in many patients [12]. In an 11-month-old infant, with normal immunoglobulins but a marked reduction in memory B cells, impaired T-cell activation and reduced T-cell subsets, infections with SARS-CoV-2 and respiratory syncytial virus triggered episodes of neurological deterioration [128].

Frequencies in the 2026 cohort

In the international cohort of 60 patients (60% classified as MOPD I, 30% as unlabelled RNU4atac-opathy, 8.3% Roifman and 1.7% Lowry-Wood), IUGR was present in 75% (36/48); microcephaly and short stature were recorded at some point in 95%; at the last assessment, 92% (45/49) had microcephaly, 47% between −5 and −10 SD, and 86.8% (46/53) short stature, 6 below −10 SD; all patients with stature below −7.5 SD had MOPD I [28]. Developmental delay was present in 92.5% (37/40), from mild to profound; 91.5% (43/47) had brain anomalies, mainly of the corpus callosum (25 patients), and 33.3% (13/39) seizures, all with a brain malformation; lissencephaly and holoprosencephaly occurred only in MOPD I [28]. The skeleton was affected in 87.8%, with mesomelia in 80% of the disproportionate patients and involvement of the spine (20/31), epiphyses (19/28) and metaphyses (13/28) [28]. Immunodeficiency was recorded in 77% (27/35), mainly hypogammaglobulinaemia (63%), and 63% received immunoglobulin; two siblings had chronic inflammatory demyelinating polyneuropathy [28]. There were skin changes in 76.2% (eczema in 21, dry skin in 14), retinal changes in 41% (16/39), strabismus in 59%, hearing loss in 36%, endocrinopathies in 50% of the 30 assessed (hypothyroidism 8, diabetes 6, almost all type 1, GH deficiency 2, adrenal insufficiency 3), minor heart defects in 22.9% with spontaneous resolution, renal changes in 37.1% and gastrointestinal changes in 60.6% (gastrostomy in 4) [28]. Twelve patients (20%) had died, between 32 weeks of gestation and 12 years, mainly from sepsis and respiratory failure [28].

The European cohort found autoimmune or inflammatory manifestations in almost half of the 69 participants and a substantial proportion of attenuated, paucisymptomatic or atypical forms [27]. In the European cohort, with 61 families from 14 countries, recurrent infections affected 74% (45/61), viral in 90% (including severe cytomegalovirus, COVID-19 and herpes simplex) and bacterial in 50%; hypogammaglobulinaemia was present in 60% (25/42), B lymphopenia in 40%, and there were combined forms with CD4, CD8 or NK lymphopenia [27]. Autoimmune or inflammatory manifestations affected 45% (29/65), 63% in the group with immunodeficiency without MPD: type 1 diabetes (7), alopecia areata (7), Hashimoto's thyroiditis (4), acute encephalitis (5), inflammatory bowel disease (4), autoimmune anaemia (4), and isolated cases of lupus, Sjögren's syndrome, antiphospholipid syndrome and neuromyelitis optica; they could appear in adulthood in people without previous complaints, and two autoimmune haemolytic anaemias required intensive care [27]. There was also GH deficiency in 50% (13/26 assessed), primary hypothyroidism in 34%, severe bronchiectasis in 5 patients (lobectomy in 2), non-malformative nephropathies in 11% (glomerulopathy, tubulopathy with magnesium and potassium wasting, steroid-resistant glomerulonephritis), progressive axonal neuropathy from 14 years of age in 5, and a nephroblastoma at 8 years [27]. Severe microcephaly was not associated with ID (odds ratio [OR] 1.3; 95% CI 0.4–4.0), unlike brain malformations (OR 6.7; 95% CI 1.3–27) and especially gyration anomalies (OR 9; 95% CI 1.7–47); even without ID, 75% of patients without MPD had learning difficulties [27]. Some patients were first diagnosed with Usher syndrome, mitochondrial disease with a Leigh pattern, interferonopathy, AIRE or FOXP3 disorders, or cystic fibrosis [27]. Another 2026 series, with 4 patients (3 adults), highlighted renal disease, autoimmunity and systemic inflammation, with markers of T-cell activation and exhaustion (HLA-DR and PD-1) [110]. Among 276 infants with diabetes, 12 had biallelic variants in RNU4ATAC; diabetes with onset in infancy, with anti-islet autoantibodies in half of those tested, became part of the spectrum [97].

3.5. Microcephalic dwarfisms due to defects of NHEJ and the replisome

In ligase IV deficiency, prenatal growth restriction is followed by extreme postnatal growth failure (11 patients with a mean HC of −10.1 SD and stature of −5.1 SD), a Seckel-like face and variable learning difficulties; thrombocytopenia and leucopenia appear in childhood, immunodeficiency ranges from silent to SCID, all cells tested are radiosensitive and there is a predisposition to lymphoid neoplasms [13, 30, 66]. In XRCC4 deficiency, short stature and severe microcephaly are present at birth and progress, with variable neurodevelopmental disorder, ataxia and seizures in some and, in adulthood, hypergonadotrophic hypogonadism, multinodular goitre and diabetes; immunoglobulins are normal and there is neither bone marrow failure nor clinical immunodeficiency, despite the V(D)J recombination defect [30, 67, 129]. A French series of 7 patients added increased nuchal translucency, congenital glaucoma, thumb anomalies, oligodontia and, in isolated cases, hyper- and hypopigmented patches and pancytopenia to the phenotype; about twenty patients have been described [30, 130]. Hypomorphic variants in DONSON cause microcephaly, variable short stature and anomalies of the upper limbs and radial ray (MISSLA), overlapping with Fanconi anaemia; the most severe forms (microcephaly-micromelia syndrome) lead to death in utero or shortly after birth [30, 68, 102, 131]. OMIM links DONSON (21q22.11) to three recessive phenotypes: microcephaly-micromelia (251230), MISSLA (617604) and Meier-Gorlin syndrome type 10 (MGORS10, 621528) [101]. The founder variant of microcephaly-micromelia, c.1047-9A>G, was found in at least 12 Cree patients from a large consanguineous First Nations lineage in Saskatchewan and later in two Saudi siblings; it is hypomorphic, because a small fraction of transcripts is spliced correctly, and it escaped exome and genome sequencing, having been identified by transcriptome sequencing [101, 102]. In the original MISSLA series (27 patients from 20 families of European, Indian, Saudi, South African, Palestinian and Turkish origin), no patient had two null variants, which points to hypomorphic alleles; the c.786-22A>G variant was present in 9 patients from 7 Saudi families, with a founder effect in 5, and a common ancestral haplotype with three variants (NM_017613.4:c.82A>C p.(Ser28Arg), c.786-33A>G and c.1466A>C p.(Lys489Thr)) was present on one allele in 7 families [68, 101]. A Palestinian family with MISSLA had been published in 1993 as Fanconi anaemia, because of the radial ray and thumb anomalies, and a 2023 review considered that some patients of the 2017 series have a phenotype closer to Meier-Gorlin syndrome [101]. In MGORS10, the variant NM_017613.4:c.631C>T p.(Arg211Cys) occurred in the homozygous state in several Turkish patients (allele frequency of 0.1% in a set of 1000 Turkish exomes), with proportionate short stature and microcephaly, microtia and absent patellae, and sometimes radial ray and genital anomalies; c.1297C>T p.(Pro433Ser) was described in a girl of Indian origin with a stature of −8 to −9 SD and HC of −5 to −6 SD [101]. A heterozygous de novo variant was described in a boy with a picture of femoral-facial syndrome, an association that OMIM includes among those awaiting replication [101]. In WDHD1-related dwarfism, 17 patients from 14 families had various additional anomalies, including acute liver failure [31].

3.6. Natural history and treated disease

The natural history data for MOPDII before 2010 include patients who died of stroke or AMI before screening programmes existed; the cohort of 47 patients already includes screened and treated patients, and the authors expect surveillance to improve the length and quality of life [26, 114]. In the review of aneurysms in MPD, the age at detection was lower in screened than in unscreened patients (p=0.02), an indirect indicator of the benefit of screening [121]. In RNU4atac-opathy, the historical mortality of MOPD I, attributed mainly to infections, was recorded without systematic immunological evaluation, and the identification and treatment of immunodeficiency may change survival [12].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

Prenatal period. In MOPDII, growth restriction is visible on ultrasound between 12 and 14 weeks and worsens until term; the short limbs and microcephaly may be noticed [26, 41]. In MOPD I, IUGR is the first anomaly, and microcephaly and agenesis of the corpus callosum are detected at about 18 weeks, accompanied by intracranial cysts, lissencephaly and micrognathia, whereas skeletal dysplasia was suggested in only one of five fetuses [29]; growth delays and microcephaly have been detected at 19 weeks [42]. A "bird-headed" profile with severe microcephaly was identified at 21 weeks on two-dimensional and three-dimensional ultrasound [132]. Severe symmetric IUGR, especially with disproportionate microcephaly, should lead to consideration of MOPDII and the other forms of the class, because fetal size may be mistaken for IUGR of placental cause [91, 133]. In primary microcephaly with normal stature, by contrast, fetal HC may fall only late in pregnancy, sometimes at 32–36 weeks [35].

Newborn and infant. A newborn weighing 1500 g or less and measuring 40 cm or less at term, with microcephaly, suggests MOPDII [36]. At this age skeletal dysplasia may not be recognisable and the characteristic nose only becomes defined during the first year [11, 26]. Feeding difficulties are universal and weight gain is very slow [11, 36]. In MOPD I, the combination of extreme microcephaly with a sloping forehead, prominent eyes, alopecia, dry skin, short limbs and severe brain malformation, with apnoeas and seizures, is characteristic [12, 42].

Child. A child with stature and HC both below −4 SD belongs to the microcephalic primordial dwarfism group; an HC proportionately more affected than stature, with moderate to severe ID and a sloping forehead, points to Seckel syndrome in the narrow sense; near-normal intelligence, with slender-bone dysplasia, coxa vara, very small teeth and a high-pitched voice, points to MOPDII [11, 35]. Recurrent sinopulmonary infections, retinal dystrophy or epiphyseal dysplasia in a patient with microcephaly point to RNU4atac-opathy, even if the microcephaly is mild or absent [12]. Thrombocytopenia, leucopenia or infections in a patient with extreme microcephalic dwarfism point to ligase IV deficiency [66]. Radial ray anomalies with microcephaly and short stature suggest DONSON and Fanconi anaemia [68, 131].

Adolescent and adult. Diabetes, hypertension, CKD and coronary events appear in adolescence and early adulthood in MOPDII; endocrinopathy (hypergonadotrophic hypogonadism, goitre, diabetes) appears in adulthood in XRCC4 deficiency; extreme insulin resistance with primary gonadal failure characterises the NSMCE2 form [11, 59, 67].

4.2. Warning signs and emergency situations

4.3. Newborn screening

There is no specific newborn screening for the disorders of this class, and none of the sources consulted describes a programme. Diagnosis starts from severe IUGR and microcephaly identified on ultrasound or at birth [26, 29]. NHEJ defects, such as ligase IV deficiency, belong to the group of radiosensitive severe combined immunodeficiencies, which are distinguished from the RAG1/RAG2 forms or those due to adenosine deaminase deficiency [86].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

No published consensus clinical criteria exist for MOPDII or for RNU4atac-opathy, and Seckel syndrome has no formal criteria [11–13]. The operational definition of the group is HC and stature both below −4 SD, with IUGR [11, 35]. The authors of the withdrawn GeneReviews chapter required, for Seckel syndrome, a birth length of −4 SD or less, and considered that a stature between −3 and −4 SD maintained after the first year defines a phenotype intermediate between primary microcephaly and Seckel syndrome [13]. In MCPH, stature is normal by definition; a stature between −2 and −3 SD defines atypical MCPH [13].

The findings that should raise suspicion of MOPDII are severe prenatal and postnatal growth restriction, extreme microcephaly, skeletal dysplasia, a prominent nose with a broad root and low columella, simple ears with attached lobes, microdontia with early tooth loss, global vascular disease, CKD, insulin resistance, hypertension, thrombocytosis, anaemia and a high-pitched voice; on imaging, mesomelia, slender long bones with progressive metaphyseal widening, delayed epiphyseal ossification, dislocation of the radial heads, brachymesophalangy, small iliac wings with flat acetabular roofs, coxa vara, slipped capital femoral epiphysis, scoliosis, moyamoya and aneurysms [11]. In RNU4atac-opathy, epiphyseal dysplasia is the minimum skeletal finding, and the combination of epiphyseal dysplasia with microcephaly is strongly discriminating, especially with immunodeficiency or retinal dystrophy [12].

5.2. Non-molecular investigations

The approach to microcephaly in the Oxford Desk Reference includes a three-generation pedigree with enquiry about consanguinity, the history of exposures in pregnancy, review of ultrasound dating, weight and HC at birth with a longitudinal chart, measurement of the parents' HC in mild microcephaly and exclusion of craniosynostosis [35]. The recommended investigations are genomic testing (array and panel, exome or genome), karyotype to look for spontaneous rearrangements typical of chromosomal instability disorders, brain magnetic resonance imaging (MRI) to look for migration anomalies, urinary organic acids and amino acids, ophthalmological assessment, investigation of congenital infections (including Zika virus) and, in suggestive settings, maternal phenylketonuria, Angelman syndrome and 7-dehydrocholesterol [35]. A radiological skeletal survey distinguishes the MOPDs, with dysplasia, from Seckel, 3M and Silver-Russell syndromes, which have slender but normally formed bones [41, 42]. Cellular radiosensitivity (chromosome breaks after irradiation) supports an NHEJ defect; in patients with LIG4, all those tested were radiosensitive [66, 86]. Spontaneous chromosome breaks and polyploidy, without hypersensitivity to cross-linking agents, have been described in the NSMCE2 form [88].

5.3. Molecular strategy

For MOPDII, when the phenotype is suggestive, PCNT sequencing detects more than 98% of pathogenic variants (28 of 29 patients in the original series; 44 of 46 in the 2021 cohort), and targeted deletion and duplication analysis detects about 1%; if sequencing finds one or no variant, deletion and duplication analysis follows [11]. A primordial dwarfism and microcephaly panel that includes PCNT and the differential diagnosis genes is the most efficient alternative; exome or genome sequencing is useful when the diagnosis has not been considered [11]. In Seckel syndrome and the other forms, the extreme genetic heterogeneity makes genomic tools the usual route to diagnosis, and it is the molecular test, not the phenotype, that defines the subtype [30, 34]. In consanguineous families, mapping of regions of homozygosity by single nucleotide polymorphism array helps to prioritise genes [13].

For RNU4atac-opathy, RNU4ATAC sequencing detects 100% of known variants; whole-gene deletions have not been described, but, with a single variant, deletion analysis may be considered [12]. A skeletal dysplasia, primordial dwarfism or microcephaly panel that includes the gene, or the genome, are the alternatives [12, 29].

5.4. Limitations of the tests

A negative result does not exclude the diagnosis. In MOPDII, a cryptic variant on the second allele may escape conventional methods and has been demonstrated by functional studies showing absence of pericentrin [11]. For RNU4ATAC, the limitations are of three kinds [12, 28]. First, coverage: only about 35% of gnomAD v4.1 exomes cover the gene at a depth greater than 5-fold, although clinical exomes cover it better. Second, analysis: even when the gene is covered, variants may be filtered out because pipelines prioritise missense and loss-of-function variants in coding genes; computational predictors of splicing and protein effect do not apply to a non-coding RNA. Third, nomenclature: the one-base-pair difference between Ensembl and NCBI and the recent introduction of the MANE transcript may generate annotation errors. In 3 of 53 undiagnosed patients with Joubert syndrome, exome reanalysis found variants in RNU4ATAC [113], and in prenatal cases the authors recommend the genome or targeted approaches beyond the standard exome [29].

The proportion of variants detectable by a method is not the clinical sensitivity of the test: the 98% for PCNT sequencing refers to the known variants in patients with a diagnosis of MOPDII, and not to the probability that a negative test excludes the disorder in a child with unclassified microcephalic dwarfism [11]. Parental mosaicism and uniparental isodisomy are rare causes of apparent homozygosity or of a variant present in only one parent [11, 12].

5.5. Reporting, classification and variants of uncertain significance

The report should state the gene, the transcript and its version, the HGVS description, zygosity, phase (cis/trans) when known and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), in which "pathogenic" and "likely pathogenic" have the same clinical value [11, 12]. In RNU4atac-opathy, two variants of uncertain significance (VUS), or one pathogenic variant with a VUS, neither establish nor exclude the diagnosis [12]. The variants are concentrated in three functional regions, and a variant close to known variants in a functional region is more likely to be relevant [12]. A cellular assay of the splicing efficiency of a reporter minor intron in fibroblasts has been developed, which is not available for diagnosis and misclassifies the variant NR_023343.3:n.124G>A, which reduces the level of the RNA itself [12, 134]. RNA-seq showed a consistent pattern of minor intron retention in all patients tested and allowed six VUS in trans with a likely pathogenic variant to be reclassified as likely pathogenic [28]. In the 2026 cohort, the ACMG/AMP criteria were applied, supplemented by the recommendations for non-coding variants; the 6 VUS "of high interest" were considered causal by combining the phenotype with the predicted effect on RNA structure, a line of reasoning that current standards do not accommodate well [28].

Parental segregation is needed to confirm phase and for counselling. If the variant is present in only one parent, with paternity and maternity confirmed, a de novo variant in the proband, parental germline mosaicism or, with apparent homozygosity, an undetected deletion or uniparental isodisomy are considered [11, 12].

5.6. Diagnostic algorithm

5.7. Prenatal and preimplantation diagnosis

With the familial variants identified, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible for MOPDII, RNU4atac-opathy and the Seckel forms [11–13]. A sibling of a child with MOPDII was diagnosed by chorionic villus sampling [133]. In a recurrence of Seckel syndrome, ultrasound can detect IUGR in the second trimester with high reliability, unlike primary microcephaly, in which HC often decreases only late in pregnancy; in a pregnancy without a family history, ultrasound alone does not distinguish Seckel syndrome from other causes of IUGR, and fetal MRI may help [13]. A series of four fetuses and four patients with RNU4ATAC variants provided prenatal descriptions, including compound heterozygous twins with only mild IUGR and atypical dysmorphic features [135]. In one of the five fetuses with MOPD I, the genetic diagnosis was obtained at 27 weeks; four pregnancies were terminated [29].

6. Differential Diagnosis

6.1. Comparative table

Sources: [11–13, 26, 35, 41, 42, 66–68, 86, 97, 113, 131, 136, 137].

6.2. Seckel syndrome, MOPDII and MOPD I compared

The three historical entities of the group are distinguished by the proportion between head and body, by the skeleton and by development. In Seckel syndrome, stature is less affected than in MOPDII, but microcephaly and ID are more pronounced, the forehead is often sloping and there are no evident skeletal anomalies [36, 41]. In MOPDII, the forehead is relatively vertical, intelligence is near normal, the ilia are tall and narrow, the metacarpals and proximal phalanges are overmodelled, and there is coxa vara and vascular disease [11, 41]. In MOPD I, the forehead is sloping, the hair sparse and the skin dry, the ilia are short and broad, the metacarpals short and square, the brain malformations are severe and the prognosis is much worse [41, 42]. Willems and colleagues showed that 5 of 16 patients with a clinical diagnosis of Seckel syndrome had PCNT variants, minor skeletal changes and a picture compatible with MOPDII; the authors of the Colombian report suggest reassessing all patients with a clinical diagnosis of Seckel syndrome [50, 91]. This distinction has consequences: according to Bober and Jackson, cerebrovascular disease is specific to MOPDII, and confirming the diagnosis with PCNT is essential for care [26].

6.3. Boundary with primary microcephaly

The distinction between MCPH and Seckel syndrome used to be made by stature: between −1 and −2 SD in MCPH and between −4 and −12 SD in Seckel syndrome. Loss-of-function variants in CPAP/CENPJ, CEP152 and PHC1 have been described in both pictures, and statures between −2 and −4 SD in patients with variants in RBBP8, CEP152, CPAP/CENPJ, CEP63 and PHC1 constitute an intermediate phenotype [13]. In a series of 150 patients with Mendelian congenital microcephaly, more than 52% of patients with primary microcephaly had short stature, and the first CEP135-related microcephalic primordial dwarfism was described [84]. Distinction by stature remains clinically useful, but does not predict the gene [13].

Saudubray includes WDR4-related microcephalic primordial dwarfism, together with WDR62-related microcephaly, in the group of deficiencies of the WD-repeat protein family, among the causes of epileptic encephalopathy in the first year of life with prominent spasticity [138].

6.4. DNA repair disorders and radiosensitivity

Seckel syndrome shares features with the disorders of the damage response, such as Nijmegen breakage syndrome and LIG4 syndrome [47]. The face in Nijmegen syndrome resembles that of Seckel syndrome, microcephaly is primary in 75% and there is immunodeficiency, translocations between chromosomes 7 and 14 and a risk of lymphoma and rhabdomyosarcoma [13, 86]. Microcephaly with SCID and short stature due to NHEJ1 (Cernunnos) or LIG4 is accompanied by hypogammaglobulinaemia, severe B and T lymphopenia and radiosensitivity [13]. Because extreme growth failure is enough to consider ligase IV deficiency, and because bone marrow failure, immunodeficiency and neoplasia are late sequelae, early recognition has preventive value [66].

6.5. Primordial dwarfism with immunodeficiency

Immunodeficiency in a child with microcephalic dwarfism points to RNU4atac-opathy, NHEJ deficiencies, IMAGe-I syndrome, cartilage-hair hypoplasia and Schimke dysplasia [11, 12]. T-cell deficiency, rather than humoral deficiency, suggests Schimke dysplasia; hypogammaglobulinaemia with epiphyseal dysplasia and retinal dystrophy suggests RNU4ATAC [12]. In adults with hypogammaglobulinaemia, the differential includes antibody deficiency secondary to drugs (valproate, phenytoin, carbamazepine, anti-B-cell therapies) and protein loss; failure of IgG to recover after withdrawal of the drug and an association with short stature, epilepsy or cardiomyopathy point to RNU4atac-opathy [107].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of the recommendations

No disorder of this class has mechanism-directed treatment, and there are no randomised trials of any intervention [30]. Management is multidisciplinary and rests on surveillance and the treatment of each complication. There are no scientific society guidelines specific to the class; for immunodeficiency, the 2025 American practice parameter for inborn errors of immunity (AAAAI/ACAAI/CIS) and the 2022 British consensus on immunoglobulin replacement (BSI/UKPIN) apply by extrapolation [139, 140]. For MOPDII, the reference is the clinical review with care recommendations by Bober and Jackson (2017), integrated and updated in the GeneReviews revised in November 2025, which added considerations for adults [11, 26]. For RNU4atac-opathy, the recommendations of the 2023 GeneReviews are based on the authors' experience with 20 patients over almost 20 years [12]. For Seckel syndrome there are no current recommendations; the 2013 chapter, withdrawn in 2018, is of historical value only [13]. The remaining forms (LIG4, XRCC4, NSMCE2, TRAIP) have guidance derived from small series [30].

7.2. Initial evaluation after diagnosis

Sources: [11–13, 26, 36, 125].

7.3. Growth and nutrition

The most frequent management error in MOPDII is to treat as "growth retardation" a growth pattern that is expected for the disorder. The expected weight gain is about 2 g/day throughout childhood, and the specific charts (Bober 2012; Duker 2017) serve to set realistic expectations [11, 118]. Gastrostomy should be avoided unless weight gain is below that expected for the disorder after the usual feeding regimens have been tried, because overfeeding by tube may cause iatrogenic oral aversion, and excessive nutritional supplementation in infancy is one of the circumstances to avoid [11]. In MOPD I, the expected gain is even lower (< 2 g/day), and gastrostomy with Nissen fundoplication may be indicated in children who do not feed orally, who aspirate or who do not achieve the expected gain [12]. In the 2026 cohort, 4 of 33 patients with RNU4atac-opathy had a gastrostomy [28].

7.4. Growth hormone

In MOPDII, GH is not recommended in the absence of GH deficiency: it did not improve final stature (11 treated patients, with no significant differences in SD for stature, weight or HC compared with untreated patients), it may contribute to morbidity, and insulin resistance was detected during treatment in at least 3 patients [11, 26, 115]. Majewski had already recorded the absence of GH and somatomedin deficiency in the original patients [39]. The Colombian report describes a trial of GH between 2 and 3 years of age, stopped for lack of response [91]. In a patient with MOPDII and acquired IGF-1 deficiency due to cirrhosis, recombinant IGF-1 was stopped at 6 months because of worsening skeletal dysplasia [26]. Smith's summarises that GH was ineffective in MOPDII [36]. For Seckel syndrome, the 2013 chapter accepted that GH could be considered in mild growth retardation, without objectively assessed efficacy [13]. In RNU4atac-opathy, documented GH deficiency was found in 2 of 30 patients assessed in the international cohort and in 13 of 26 patients tested in the European cohort [27, 28]. Documented deficiency is a labelled indication for somatropin, with paediatric doses of 0.025–0.035 mg/kg/day or 0.7–1.0 mg/m²/day in the European SmPC and 0.16–0.24 mg/kg/week, in 6–7 subcutaneous injections, in the FDA label [141, 142]. There are no series of treated patients; the only report found is that of a Chinese boy with multiple epiphyseal dysplasia and GH deficiency, carrying variants in RNU4ATAC, PLEC and CD96, who grew 18 cm over 25 months of treatment, to 137 cm at 13 years and 11 months, with a 5-year advance in bone age; the contribution of each gene was not demonstrated [143]. Because JAK1/STAT5 signalling, required for the response to GH, is attenuated in cells from patients with Roifman syndrome, the response (growth velocity and IGF-1) should be reassessed before treatment is prolonged [99].

A child with MPD born small for gestational age (SGA) may formally meet the SGA indication in the labels. In the European Union, Omnitrope® (somatropin) is indicated in SGA children with stature below −2.5 SD, parent-adjusted stature below −1 SD, birth weight and/or length below −2 SD and no catch-up growth by 4 years or later, at the usual dose of 0.035 mg/kg/day (1 mg/m²/day) until final stature, with no maximum dose defined in the SmPC for this indication; treatment is stopped if growth velocity at the end of the first year is below +1 SD [141]. The SmPC requires other medical causes to be excluded before starting, fasting insulin and glucose to be measured before and annually, an oral glucose tolerance test in patients with severe insulin resistance or acanthosis nigricans, GH not to be given in overt diabetes and monitoring for slipped capital femoral epiphysis and progression of scoliosis [141]. In the United States, Genotropin® is indicated in SGA children without catch-up growth by 2 years, at doses up to 0.48 mg/kg/week, with warnings about glucose intolerance, slipped epiphysis and scoliosis [142]. These warnings coincide with the complications specific to MOPDII (insulin resistance in 18 of 21 patients, slipped epiphysis and coxa vara, scoliosis), which reinforces the recommendation of the specific sources not to treat [11, 116, 117].

7.5. Cerebrovascular disease in MOPDII

Screening. Brain MRI with MR angiography (MRA) of the circle of Willis, the cervical arteries and the great vessels is the preferred method, and the first examination is performed at diagnosis, including in the neonatal period, because there are intrauterine strokes and neonatal moyamoya [11, 26]. MRA is sensitive for clinically relevant moyamoya, and aneurysms below its resolution would hardly be candidates for treatment [26]. The proposed intervals diverge: Perry and colleagues propose annual examinations until 10 years and every 2 years thereafter, for life; Bober and colleagues proposed, in 2010, at least every 12–18 months with MRA or computed tomography angiography; the 2017 review recommends annual examinations in the first decade and every 12–24 months in the second; the 2025 GeneReviews recommends every 12–18 months in childhood and every 12–24 months in adulthood [11, 26, 119, 120]. All sources agree that screening has no end age and that a first finding does not make future examinations unnecessary, because the same patient may have several lesions at different times [26, 120]. Any acute neurological symptom or cognitive decline justifies immediate imaging [26, 119].

Moyamoya. Indirect revascularisation, mainly encephaloduroarteriosynangiosis (EDAS) and pial synangiosis, is technically possible and strongly indicated to prevent sequelae, and treatment is needed mainly in childhood [11, 26]. In the Stanford surgical series (2005–2012), 8 patients with moyamoya (mean age 9 years, 1–17) underwent 14 indirect revascularisations and 1 direct revascularisation, and 5 patients with aneurysms (mean age 15.5 years, 9–18) underwent surgery; there was one transient weakness after clipping and one femoral thrombosis requiring surgical repair, and during a mean follow-up of 5.9 years 3 patients died (subarachnoid haemorrhage, AMI and respiratory failure), whereas the survivors recovered their baseline neurological status [144]. Microneurosurgery in these patients, with tiny arteries and narrow surgical corridors, is extremely difficult and is feasible only in specialist centres [144].

Aneurysms. Treatment is by microsurgical clipping or endovascular embolisation with coils or stent, depending on location, in childhood and adulthood [11, 26]. In the systematic review of aneurysms in MPD, clipping was the most frequently used modality (55.3%), followed by embolisation (26.3%), and 22 cases were managed conservatively [121]. In the review of patients labelled as Seckel syndrome, 2 of 4 endovascularly treated aneurysms bled again and were fatal, and the authors recommend case-by-case decisions [37]. Various anticoagulants have been tried as non-surgical treatment, without efficacy data [26].

Blood pressure and perfusion. Hypertension probably aggravates aneurysm formation, but, in a patient with moyamoya, a moderate reduction in cerebral perfusion may cause ischaemic stroke, which makes blood pressure control delicate [11, 26].

7.6. Blood pressure, heart and kidney in MOPDII

The definition of hypertension in these patients is not known, because the norms depend on stature, and adult thresholds are probably too high. Duker and colleagues propose 110/70 mmHg as the initial upper limit in adults, especially in the presence of neurovascular disease, CKD or diabetes, measured with an appropriately sized cuff; in children, values moderately elevated for age norms are probably pathological [11, 26, 114]. Hypertension and hypercholesterolaemia were treated with medication, and the sources do not specify drugs or doses [11]. Coronary disease was treated with stents and bypass surgery; professionals should be alert to AMI in young adults, for immediate treatment [11, 114]. CKD was treated with medication, dialysis or kidney transplantation [11]. Femoral occlusion after catheterisation, described in at least 6 patients, calls for care with arterial access [11, 144].

7.7. Insulin resistance and diabetes

Diabetes in MOPDII was treated in most cases with metformin and/or insulin; the sources do not give specific doses for this population, and GeneReviews recommends that, in adults with the body of a small child, drugs be dosed by weight [11]. In NSMCE2 syndrome, management is dominated by insulin resistance, hypertriglyceridaemia, steatosis and gonadal failure, with hormone replacement [30, 59]. In RNU4atac-opathy, early-onset diabetes is mainly autoimmune, with anti-islet autoantibodies in half of the patients tested, and was classified as type 1 in 5 of 6 patients of the 2026 cohort [28, 97].

7.8. Skeleton and teeth

Coxa vara in MOPDII was treated with in situ fixation (three patients, mean age 4 years) or valgus osteotomy (one patient with bilateral coxa vara, at 5 years), with good results; a bilateral developmental dislocation was treated by open reduction and casting, with coxa valga two years later [26, 117]. Scoliosis was treated by instrumented posterior spinal fusion [11]. In RNU4atac-opathy, orthopaedic treatment is standard, preferably at a skeletal dysplasia centre, and patients who walk should limit repetitive impact activities to preserve the joints and reduce the pain of epiphyseal dysplasia [12]. Dental care begins as soon as teeth are present and takes place every 6 months; rehabilitation with dentures or small implants, with a prosthodontist, is usually needed in late adolescence or early adulthood [11, 26].

7.9. Immunodeficiency in RNU4atac-opathy and in the forms with NHEJ deficiency

Immunodeficiency is the most actionable element of RNU4atac-opathy: it should be sought in all patients, regardless of the clinical label, because early detection and treatment can be life-saving [12]. The immunological evaluation is carried out before any live vaccine [12]. Treatment follows the immunologist's guidance, with immunoglobulin replacement when indicated, prompt treatment of bacterial infections and, in some patients, antimicrobial prophylaxis [12]. In the 2026 international cohort, 17 of 27 patients with immunodeficiency (63%) received immunoglobulin [28]; in the European cohort, 26 of 41 (63%) received immunoglobulin replacement and/or antimicrobial prophylaxis with azithromycin or co-trimoxazole, without doses described [27]. The only n.51G>A homozygote with prolonged survival (more than 12 years, when the typical age at death is 0 to 3 years) received immunoglobulin from an early age, and the authors propose evaluating whether immunomodulatory therapy improves survival in MPD; this is a hypothesis based on a single case [27]. The authors of a 2026 case with combined immunodeficiency and encephalopathy triggered by viral infections advocate early immunological evaluation and timely prophylaxis [128].

There are no doses validated specifically in RNU4atac-opathy; those for inborn errors of immunity with IgG antibody deficiency apply by extrapolation. The 2025 American practice parameter (AAAAI/ACAAI/CIS) recommends immunoglobulin replacement in all inborn errors with IgG antibody deficiency (strong recommendation, high certainty), with an initial dose of 400–600 mg/kg per month — intravenously every 3–4 weeks or subcutaneously divided into weekly or fortnightly administrations —, adjustment to clinical response and to weight changes greater than 5%, and maintenance of serum IgG above 800 mg/dL (8 g/L) [139]. The British BSI and UKPIN consensus sets as the initial target an IgG trough of at least 8 g/L in primary deficiencies and of 10 g/L when there is organ damage, such as bronchiectasis, or persistent infections [140]. In the British adult with Roifman syndrome diagnosed at 45 years, replacement reduced infections and respiratory exacerbations, and the dose was later reduced while maintaining the trough above 8 g/L [107].

For prophylaxis with azithromycin, the same parameter gives 5 mg/kg/day (maximum 250 mg/day) or 500 mg three days a week and accepts in adults 250 mg three days a week or 250 mg daily, with co-trimoxazole or amoxicillin as alternatives (conditional recommendation, low certainty), after non-tuberculous mycobacterial infection has been excluded and with monitoring of the corrected QT interval [139]. In the Italian randomised trial in primary antibody deficiencies with chronic lung disease, low-dose azithromycin (250 mg three times a week for 2 years) reduced respiratory exacerbations from 5.2 to 3.6 per patient-year compared with placebo (89 patients), with a comparable safety profile [145]. Prophylactic co-trimoxazole against Pneumocystis jirovecii, indicated only in forms with relevant T-cell deficiency, uses one double-strength tablet (800/160 mg) daily in adults and, in children, 750 mg/m²/day of sulfamethoxazole with 150 mg/m²/day of trimethoprim in two doses, on three consecutive days a week, up to a maximum of 1600/320 mg/day [146]. The hypothesis of using JAK inhibitors for the autoimmune or inflammatory manifestations, raised by the European cohort, has no clinical data in these disorders, and the reduction in JAK1 and STAT5 phosphorylation in cells from patients with Roifman syndrome suggests an already hypofunctional pathway, in which further inhibition could worsen the immunodeficiency [27, 99].

The immunoglobulin labels serve as a comparison with the guideline doses:

The label risk factors for thrombosis and renal injury (diabetes, kidney disease, cardiovascular risk) are relevant in patients with RNU4atac-opathy who have diabetes or renal changes [28, 148]. In ligase IV deficiency, management includes prophylaxis and treatment of infections, transfusion and haematological support and surveillance for lymphoid neoplasia; haematopoietic stem cell transplantation is the only approach capable of correcting the immunodeficiency and bone marrow failure, with limited experience [30, 149]. In LIG4 and XRCC4 deficiency, unnecessary ionising radiation should be avoided, and radiotherapy requires specialist advice [30].

7.10. Neurology, anaesthesia and perioperative care

Seizures are treated with the usual antiepileptic drugs chosen by the neurologist; in the MCPH–Seckel spectrum they generally responded to monotherapy [12, 13]. In MOPD I, hydrocephalus and interhemispheric cysts may require shunting [12]. Methylphenidate (Ritalin®) was reported as useful for marked hyperkinesis in the MCPH–Seckel spectrum, without specific dose data [13].

In MOPD I, strokes occur in situations of physiological stress, including anaesthesia; situations of medical stress should be kept to a minimum and unnecessary anaesthesia avoided [12]. Intubation may be difficult in patients with a small chin, as has been reported in Seckel syndrome [13, 150]. In MOPDII, cerebrovascular disease, hypertension and coronary disease should be known before any procedure, blood pressure should be measured with an appropriate cuff, stents and intubation equipment should be of an appropriate size and femoral access requires care, given the frequency of femoral occlusion after catheterisation [11]. In a patient with moyamoya, hypotension may precipitate ischaemia [26].

7.11. Development and education

Early intervention (occupational therapy, physiotherapy, speech and feeding therapy) is indicated from the first years, followed by an individual education plan with physical adaptations for short stature and small hands, and with vision and hearing consultants when there are sensory deficits [11, 12]. In MOPDII, attendance at mainstream schools is the rule, but independent living in adulthood is difficult; guardianship, a healthcare power of attorney or supported decision-making should be planned before 18 years of age [11].

7.12. Adults, transition and emergencies

Adults with MOPDII have a head the size of an infant's and the body of a small child, and are likely to need emergency care, for intracranial haemorrhage or AMI, precisely at the age of transition [11]. Adult-only hospitals often lack appropriate equipment: stents and intubation equipment should be of paediatric size, drugs should be dosed by weight and the availability of specialists with paediatric training is critical [11]. GeneReviews recommends giving the patient or family a letter from the treating physicians that alerts emergency teams to the potentially fatal complications, defining before transition, with paediatric cardiology and neurosurgery, where emergency care will be provided, and considering a lasting power of attorney for healthcare [11]. A 2025 report illustrates the problem: a 30-year-old man weighing 11.5 kg, labelled as having Seckel syndrome and with an embolised intracranial aneurysm, had an ST-segment elevation AMI; thrombolysis was contraindicated by the aneurysm, percutaneous coronary intervention was impossible for lack of compatible equipment, and the patient died [126].

7.13. Agents and circumstances to avoid

7.14. Pregnancy and lactation

Up to 2017 no pregnancies had been documented in women with MOPDII nor paternity in men, and in 2013 no patient in the MCPH–Seckel spectrum was known to have reproduced [13, 26]. The sources consulted have no data on pregnancy, lactation or contraception in these disorders. The precocious puberty and premature ovarian insufficiency described in MOPDII, the primary gonadal failure of the NSMCE2 form and the hypergonadotrophic hypogonadism of XRCC4 deficiency should be considered in the endocrinology and reproductive health consultation [26, 36, 59, 67].

7.15. Regulatory status

There are no authorised medicines for any disorder of the class in the United States or the European Union. The medicines used in supportive treatment with a relevant indication are the following.

7.16. Trials, registries and developments in the last 12 months

No trials of targeted therapies were found on ClinicalTrials.gov for any entity of the class; negative searches do not prove that no studies exist in other registries [151–153].

These studies have no therapeutic outcomes, and there are no results with confidence intervals to present. The only comparisons with a control group are retrospective and small (GH-treated versus untreated in 26 patients with MOPDII), and do not allow effects to be estimated [115].

The developments from November 2025 to October 2026 are all observational studies in humans or preclinical studies, with no authorisation, opinion or regulatory application:

• RNU4atac-opathy cohorts (published observational studies, 2026). The international cohort of 60 patients described the frequency of the manifestations, the 20% mortality and the usefulness of RNA-seq in reclassifying VUS [28]; the European cohort of 69 participants found autoimmune or inflammatory manifestations in 45% and proposed a classification centred on immunodeficiency and primordial dwarfism; the authors hypothesise that the accumulation of transcripts with retained U12 introns triggers sterile inflammation via the type I interferon pathway, with possible interest in the JAK inhibitors used in the interferonopathies — a hypothesis without treatment data [27]; a series of 4 patients, 3 of them adults, reinforced the correlation between the 5' stem-loop and severity [110].
• Autoimmune diabetes due to RNU4ATAC and RNU6ATAC (published genetic study, 2026). Twelve infants with diabetes had biallelic variants in RNU4ATAC [97].
• Prenatal diagnosis of MOPD I (case series, 2026). Detection of IUGR, microcephaly and agenesis of the corpus callosum at about 18 weeks and the need for genome sequencing or targeted tests [29].
• New genes and variants (genetic and cellular studies, 2026). WDHD1 in 17 patients [31]; a homozygous tandem duplication in NSMCE2 detected by genome sequencing [88]; a third patient with NSMCE2 and maculopathy [87]; RNU4ATAC variants in Joubert syndrome (2025) [113].
• Case reports (2025–2026). Prenatal diagnosis of MOPDII by chorionic villus sampling in a sibling [133]; fatal AMI in an adult with microcephalic dwarfism [126]; neurological deterioration triggered by infections in RNU4atac-opathy [128].
• Preclinical (2026). Extraneurological characterisation of mice with Cep152 variants, a model of Seckel syndrome [154]; a Drosophila U4atac model with intron retention in the JAK homologue and reduced JAK1 and STAT5 phosphorylation in cells from patients with Roifman syndrome, with ex vivo data from 3 to 5 patients per assay [99].
• Clinical case (November 2025). Roifman syndrome diagnosed at 45 years by genome sequencing, after hypogammaglobulinaemia attributed to valproate and dilated cardiomyopathy [107].

7.17. Recommendations and divergences between sources

In immunoglobulin replacement, the IgG trough target differs between sources: at least 6 g/L or within the reference range for age in the European SmPC for Privigen®, above 8 g/L in the 2025 American practice parameter and at least 8 g/L, or 10 g/L with organ damage, in the 2022 British consensus; the guidelines take precedence over the label [139, 140, 147]. The sources agree on cerebrovascular screening at diagnosis and without an end point in MOPDII, metabolic surveillance from 5 years, immunological evaluation in RNU4atac-opathy and not using GH in MOPDII [11, 12, 26, 120]. They diverge on the interval of cerebrovascular screening after 10 years (2 years for Perry; 12–18 months for Bober in 2010; 12–24 months in the second decade for Bober and Jackson in 2017; 12–24 months in adulthood for the 2025 GeneReviews), on the hypertension threshold (110/70 mmHg in adults according to Duker and colleagues, versus interpretation by age, stature and sex norms according to Bober and Jackson) and on the usefulness of vascular screening outside MOPDII: GeneReviews does not recommend it in RNU4atac-opathy, because the strokes do not follow vascular territories and the vascular anatomy is normal, whereas the review of patients labelled as Seckel syndrome considers it justifiable where resources allow [11, 12, 26, 37, 114, 119, 120]. On GH in Seckel syndrome, the only reference (2013) accepts considering it in mild growth retardation, without assessed efficacy [13].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All disorders of the class covered in this article are autosomal recessive. When both parents are heterozygous, each sibling of the proband has, at conception, a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier; a sibling known to be unaffected has a 2/3 probability of being a carrier [11–13]. The parents' siblings have a 50% probability of being carriers [11]. The children of a patient with MOPDII are obligate carriers, and in RNU4atac-opathy they are too, unless the partner is a carrier or affected [11, 12]. Heterozygous carriers are asymptomatic [11, 12]. For a couple with a child with undiagnosed primary microcephaly, after exclusion of syndromic and environmental causes and with a structurally normal MRI, the Oxford Desk Reference proposes an empirical recurrence risk of 15–20%, and of 25% if there is consanguinity [35].

Three situations change this picture. First, the variant may be present in only one parent because it arose de novo in the proband or because of parental postzygotic mosaicism [11, 12]. Second, apparent homozygosity may result from an undetected deletion on the other allele or from uniparental isodisomy [12, 91]. Third, some genes have allelic disorders with different inheritance: heterozygous ATR variants in the FAT domain cause a dominant syndrome of predisposition to oropharyngeal cancer, those of DNA2 a dominant progressive external ophthalmoplegia and, possibly, heterozygous missense variants of PCNT increase the risk of intracranial aneurysms; carriers of the usual recessive variants of these genes do not have these established risks [11, 30, 93, 105, 111].

8.2. Cascade testing and carriers

Carrier testing in at-risk relatives requires prior identification of the familial variants [11, 12]. Testing of the reproductive partner of a carrier or of a patient may be considered, especially in populations with founder variants: RNU4ATAC n.51G>A in the Ohio Amish, PCNT c.3465-1G>A in the Druze of northern Israel, PCNT c.1468C>T in Colombia, CEP152 c.261+1G>C in Turkey and the RBBP8 variant of Jawad syndrome in Pakistan [11–13, 30, 100]. The study of the Druze variants was triggered by a single child and showed carriers in several villages, which illustrates the value of population-specific sequencing databases [100].

8.3. Prenatal and preimplantation diagnosis

Once the familial variants are known, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible; opinions on their use vary between professionals and families and the decision is a personal one [11, 12]. Ultrasound can detect a recurrence of Seckel syndrome in the second trimester by the severity of the IUGR, but does not distinguish Seckel syndrome from other IUGR in a pregnancy without a family history; in MOPDII, the restriction is visible from 12–14 weeks; in MOPD I, IUGR, microcephaly and agenesis of the corpus callosum are visible at about 18 weeks [13, 26, 29]. Without a molecular diagnosis, ultrasound is unreliable in primary microcephaly, because fetal HC may fall only at 32–36 weeks [35]. The ideal time for counselling on the risks and reproductive options is before pregnancy, and it should be offered to young adults who are affected, carriers or at risk of being carriers [11, 12]. Storage of DNA from undiagnosed patients allows them to benefit from future techniques [13].

8.4. Minors and undiagnosed cases

Carrier status is not associated with health problems in these recessive disorders, and the sources direct counselling on carrier status and reproductive options to young adults; they do not specifically address testing of asymptomatic minors [11–13]. In families in which the exome was negative, reanalysis with attention to non-coding genes, genome sequencing and contact with research groups make it possible to reach a diagnosis; Andrew Jackson (Edinburgh) has expressed interest in patients with microcephalic dwarfism without an identified cause [12, 28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the figures measure

There are no population prevalence studies for any disorder of the class. The available figures are counts of published or registered cases, which measure recognition and access to molecular diagnosis, and not the true frequency. MOPDII is the most frequent form: more than 150 molecularly confirmed patients in many populations, and Orphanet records point prevalence as unknown [11, 15, 26]. For Seckel syndrome, Orphanet records about 50 cases or families and a birth prevalence in Europe of 0.2/100,000 from the EUROCAT congenital anomaly registry (2005–2012), a surveillance figure based on clinical diagnosis, which therefore includes other forms of MPD [14]. The same entry assigns Seckel syndrome a point prevalence class of 1–5/10,000, based on a systematic review that cites "almost 1 in 10,000 children" from a case report; this value has no epidemiological basis and is incompatible with the case count, so it is not used as a prevalence [14, 37]. In 2023 about 40 patients with molecularly confirmed Seckel syndrome had been published [25].

For RNU4atac-opathy, fewer than 100 patients had been published in 2020; the 2026 cohorts, with 60 and 69 participants, suggest that the mild forms are underdiagnosed, in part because the gene is not analysed in many exomes; in the European cohort, the diagnosis was made by genome sequencing in 35% and by targeted Sanger sequencing in 10%, versus 80% by targeted Sanger in the earlier literature, and the proportion of severe forms was lower [12, 27, 28]. Referrals came from specialties as diverse as rheumatology, nephrology, respiratory medicine and internal medicine [27]. Allele frequencies in population databases suggest that the recessive disorders due to RNU4ATAC may be more prevalent than reported [64]. Orphanet records 53 cases of MOPD I and III (prevalence below 1/1,000,000), 17 of Roifman syndrome and 8 of Lowry-Wood syndrome [16–18]. Primary microcephaly, the boundary of the class, has an estimated incidence of 1:30,000 to 1:250,000 [13].

9.2. Founder populations and geographical data

The MOPDII cohort of 47 patients and the growth charts come mainly from a North American registry; the Colombian patient was below −2 SD on these charts, which the authors attribute to the variant or to population origin [91, 114, 115]. European data come mainly from France (2010 series of 24 families, 2026 French and European cohort), Germany (original PCNT series) and the United Kingdom (patients with ATR) [27, 48, 50, 57]. Orphanet records European birth prevalence data from EUROCAT for Seckel syndrome [14]. From Brazil, the sources consulted include the description, by a Brazilian group, of the DNA2-related Rothmund-Thomson-like syndrome, allelic to Seckel syndrome 8 [112]. The sources consulted contain no data from Portugal.

9.3. Special populations

Adults with MOPDII are a special population: they have the body of a small child and adult complications (AMI, CKD, diabetes), and the health system is not prepared for them [11, 126]. Children with RNU4atac-opathy and immunodeficiency are vulnerable to severe infections and to stroke in stressful situations [12]. In consanguineous populations, the probability of recessive disease and the yield of homozygosity mapping are greater [13, 35].

9.4. Reference networks and patient associations

In the European Union, the relevant European Reference Networks are ERN ITHACA (rare congenital malformations and rare intellectual disability, https://ern-ithaca.eu/) and ERN BOND (rare bone diseases, https://ernbond.eu/) [32, 33]. The patient associations are the Walking With Giants Foundation (United Kingdom, dedicated to primordial dwarfism, www.walkingwithgiants.org), the Potentials Foundation (www.potentialsfoundation.org), Little People of America (lpaonline.org) and Little People UK (littlepeopleuk.org) [11, 12, 35]. The Primordial Dwarfism Registry (Nemours, Wilmington, Delaware; NCT04569149) and the International Skeletal Dysplasia Registry (UCLA) accept patients from all over the world [11, 151].

10. Illustrative Clinical Case

10.1. MOPD type II due to a Colombian founder variant of PCNT

In 2014, Pachajoa, Ruiz-Botero and Isaza described a Colombian boy of mixed ancestry, the first child of parents with common ancestry, both from a small town in the east of the department of Antioquia; the father was 36 years old and the mother 30 [91]. Ultrasound at 25 weeks showed symmetric IUGR without haemodynamic compromise, ventriculomegaly, oligohydramnios and a single umbilical artery; at 35 weeks the biometry remained below the 3rd percentile. The mother received corticosteroids for lung maturation at 28 weeks, and at 36 weeks a caesarean section was performed for premature rupture of membranes. The newborn weighed 1310 g and measured 37 cm, both below the 3rd percentile.

Psychomotor development was delayed: he crawled at 12 months and walked at 17. At 2 years he started GH, stopped a year later for lack of improvement. At 4 years, computed tomography showed microcephaly and closure of the metopic and sagittal sutures, with patent coronal and lambdoid sutures; abdominal ultrasound and echocardiography were normal. At 5 years, the patient had microcephaly, downslanting palpebral fissures, a prominent nose with a convex profile and a prominent, narrow tip, a high-arched palate, amelogenesis imperfecta, ears with a poorly developed helix and superior crus of the antihelix, bilateral clinodactyly, ulnar deviation of the hands, a high and narrow pelvis, disproportionately short forearms and legs, mild coxa vara, a high-pitched voice and a sociable personality. At 5 years and 7 months he measured 72 cm, weighed 6.7 kg and had an HC of 41.2 cm; his stature was below −2 SD on the MOPDII-specific charts of Bober and colleagues.

Sequencing of the 47 coding exons of PCNT (transcript then used NM_006031.5), performed in an accredited laboratory in Chicago, identified in exon 10 the variant c.1468C>T, which creates a stop codon at position 490 (p.Q490X), in apparent homozygosity; the authors noted that a deletion on the other allele was not excluded, but considered homozygosity more likely given the parents' common ancestry [91]. On the current MANE transcript, the variant is described as NM_006031.6:c.1468C>T, p.(Gln490Ter), with the same numbering [95]. The authors presented it as novel and accepted that the severity of the short stature might be related to the variant or to the population, noting other similar patients in the same community; the 2025 GeneReviews classifies it as a Colombian founder variant [11, 91]. Figure 1 of the article shows the patient at 5 years, with the ulnar deviation of the hands (https://pmc.ncbi.nlm.nih.gov/articles/PMC4086705/figure/F1/), and Figure 2 the electropherogram of the variant (https://pmc.ncbi.nlm.nih.gov/articles/PMC4086705/figure/F2/).

10.2. Reading the case in the light of current recommendations

The case brings together the prenatal warning signs of MOPDII: severe symmetric IUGR, which may be mistaken for growth restriction of placental cause, and a birth length much more affected than weight [91, 115]. Two management decisions described in the report do not correspond to current recommendations. GH, tried at 2 years, is not recommended in the absence of GH deficiency, because of lack of benefit and the risk of worsening insulin resistance [11, 26]. The report does not mention cerebrovascular screening, which is now recommended at diagnosis with MRI and MR angiography and then periodically and without an end point, nor metabolic and renal surveillance from 5 years [11, 26]. Comparison of growth with the specific charts, carried out by the authors, is the recommended practice to adjust expectations and avoid excessive nutritional interventions [11].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

MOPDII. Life expectancy is reduced by the vascular, renal and metabolic comorbidities, which, untreated, lead to death mainly in early adulthood (7 to 41 years in the cohort of 47 patients); in 2017, the oldest molecularly confirmed patient was 39 years old [11, 26]. About half of the patients with moyamoya or aneurysms have a stroke, cerebrovascular disease caused the death of 23% of the patients with CNS vascular disease described up to 2013, and 17% had an AMI at a mean age of 24 years [11, 26, 114]. Cognition remains in the typical to borderline range, except after stroke [11]. Screening allows aneurysms to be detected earlier, and surgical series show recovery of baseline neurological status in surviving operated patients [121, 144].

Seckel syndrome. There are no life expectancy data; anecdotal reports describe survival beyond 50 years without evident complications [13]. The haematological risk (myelodysplasia, acute myeloid leukaemia) has not been quantified or linked to a genotype [13, 124]. The TRAIP form had one death at 10 years from chronic lung disease, and the NSMCE2 form with a structural duplication led to the death of two siblings in adolescence [60, 88].

RNU4atac-opathy. In MOPD I, most children historically died in the first 1 to 2 years, mainly from infections; adults have been described, and survival seems to depend on genotype and on treatment of the immunodeficiency [12, 36, 42, 127]. In the 2026 cohort of 60 patients, 20% had died (from 32 weeks of gestation to 12 years), mainly from sepsis and respiratory failure, all with genotypes exclusively at positions 50, 51 or 55 [28]. The Roifman and Lowry-Wood forms and the attenuated phenotypes reach adulthood, with immunological, renal, pulmonary (bronchiectasis) and autoimmune morbidity, and the cognitive prognosis depends more on brain malformations than on the degree of microcephaly [27, 110].

NHEJ and replisome deficiencies. In ligase IV deficiency, bone marrow failure, immunodeficiency and lymphoid neoplasia are long-term sequelae [66]. In XRCC4 deficiency, endocrinopathy appears in adulthood [30]. Microcephaly-micromelia syndrome is lethal in the perinatal period [30].

11.2. Surveillance table

11.3. Long-term follow-up

Follow-up in MOPDII centres on three axes: lifelong cerebrovascular screening, cardiovascular, renal and metabolic surveillance from 5 years and preparation for the transition to adulthood, with an emergency plan [11, 26]. In RNU4atac-opathy, the axis is immunological and ophthalmological, with increasing attention to autoimmunity and diabetes [12, 27, 97]. In Seckel syndrome, follow-up is neurological and developmental, and haematological surveillance is justified by the description of myelodysplasia and leukaemia, even though the risk has not been quantified [13, 36].

12. Summary and Final Considerations

Microcephalic primordial dwarfism brings together autosomal recessive disorders in which growth failure begins in fetal life and head circumference and stature are both below −4 SD. The eponym "Seckel syndrome", used for decades for almost all these children, now mainly designates a group of forms with microcephaly more severe than the short stature and moderate to severe intellectual disability, caused by genes of ATR signalling, the centrosome and replication (ATR, ATRIP, RBBP8, CPAP/CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, NSMCE2, CEP295), with few patients per gene and a continuous boundary with primary microcephaly. MOPDII, caused by loss of function of pericentrin, is the most frequent and best described form: slender-bone dysplasia with coxa vara and scoliosis, very small teeth, near-normal intelligence and a global vascular disease, with moyamoya, aneurysms, early coronary disease and kidney disease, together with insulin resistance and diabetes. RNU4atac-opathy, caused by variants in an RNA of the minor spliceosome, ranges from MOPD I, with severe brain malformations and high mortality, to Roifman and Lowry-Wood syndromes and attenuated forms, and its most actionable manifestations are immunodeficiency, autoimmunity and early-onset diabetes.

Diagnosis is molecular. PCNT sequencing identifies almost all patients with MOPDII, but the other forms require panels, exome or genome sequencing, and RNU4ATAC escapes many exomes because of lack of coverage or filters that ignore non-coding genes. The distinction between the entities has direct consequences: cerebrovascular screening by MRI and MR angiography from diagnosis and without an end point, surveillance of blood pressure with specific thresholds, of renal function and of metabolism from 5 years and the preparation of emergency care in adulthood apply to MOPDII; immunological evaluation before live vaccines, immunoglobulin replacement and caution with anaesthesia apply to RNU4atac-opathy; radiosensitivity and the risk of bone marrow failure guide the management of ligase IV deficiency. Growth hormone is not indicated in MOPDII. There are no targeted therapies or ongoing trials, and knowledge continues to depend on international registries and on cohorts that, in 2026, broadened the clinical spectrum of RNU4atac-opathy and added new genes to the class.

13. References

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