Alazami Syndrome (LARP7)

Microcephalic primordial dwarfism, Alazami type, due to biallelic loss of function of LARP7, with Alazami–Yuan syndrome (TAF6), the MEPCE-associated neurodevelopmental disorder and the other microcephalic primordial dwarfisms in the differential diagnosis

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

Alazami syndrome is an autosomal recessive disorder of neurodevelopment and growth caused by biallelic loss-of-function variants in the LARP7 gene, which encodes the chaperone of the 7SK non-coding ribonucleic acid (RNA). The table identifies the main entity and the two entities that, by name or by mechanism, are confused with it. OMIM denotes the Online Mendelian Inheritance in Man catalogue; ORPHA, the Orphanet code; MONDO, the Mondo Disease Ontology; ICD, the International Classification of Diseases; HGNC, the HUGO Gene Nomenclature Committee; ERN, the European Reference Networks.

1. Introduction

1.1. Definition

Alazami syndrome is defined, in the Orphanet description, as a rare form of primordial dwarfism, often microcephalic, characterised by short stature, global developmental delay, ID of variable degree and a recognisable facies: triangular face, prominent forehead, deep-set eyes, low-set ears, broad nose, malar hypoplasia, wide mouth, thick lips and widely spaced teeth [1]. The term "primordial dwarfism" denotes disorders in which growth restriction begins in the prenatal period and persists after birth, proportionally affecting the body and, to a variable degree, the skull [22]. The 2026 reviews reduce the definition to a cardinal triad — short stature, ID and facial dysmorphism — and stress that height may range from primordial dwarfism (height below −3.5 SD) to a moderate deficit (below −2.5 SD) [5]. The expression "recessively inherited neurodevelopmental disorder with growth restriction" describes the published spectrum more accurately than "primordial dwarfism", because there are patients with normal prenatal growth and some adults with near-normal stature [13, 23].

1.2. Founding description and first reports

The first association between biallelic LARP7 variants and ID emerged in 2011, in the sequencing study of consanguineous Iranian families by Najmabadi and colleagues, which included LARP7 among fifty new genes of recessive ID; in that family, two siblings with severe ID were homozygous for the variant c.827dup, notated by Wojcik and colleagues as p.(Lys277GlufsTer7) [24, 25]. The family segregated severe ID and microcephaly, and the study published no further clinical data; OMIM records the allele with the historical notation Lys276fs, which corresponds, in current normalisation, to NM_016648.4:c.827dup p.(Lys277GlufsTer7) [4, 6]. The article that gave the syndrome its name was published in 2012 by Anas Alazami, Fowzan Alkuraya and colleagues at the King Faisal Specialist Hospital and Research Center in Riyadh: they described a large, consanguineous Saudi family with several affected members, with primordial dwarfism, severe ID and a distinctive facies, and identified a homozygous seven-nucleotide duplication, NM_016648.4:c.1024_1030dup p.(Thr344LysfsTer9) [6, 9]. The family, from the southern province of Saudi Arabia, had ten affected children in three related branches, all with growth parameters below −3.5 SD. Genetic linkage analysis in six affected siblings delimited a 26.5 Mb autozygous region at 4q24–q28.2, with a maximum multipoint LOD of 4.456, and the variant, located in exon 8, segregated with the disease and was absent from 188 Saudi controls, from 194 exomes in a local database and from the 1000 Genomes Project [3, 4, 9]. The work proposed a new mechanism of primordial dwarfism — depletion of the 7SK non-coding RNA through loss of its chaperone — and added it to the pathways already known (mitotic mechanics, IGF2 expression, the deoxyribonucleic acid (DNA) damage response, the spliceosome machinery and replication licensing) [9].

1.3. Independent confirmation and phenotypic expansion (2015–2023)

The first independent confirmations appeared in 2015 and 2016. Hollink and colleagues described two patients identified by diagnostic exome sequencing, one Dutch and one Saudi, both with frameshift variants, and broadened the spectrum to only moderately reduced growth [26]. Ling and Sorrentino published in 2016 the first patient of European ancestry, the daughter of non-consanguineous parents from the United States (US), compound heterozygous for c.213_214dup and c.651_655del, with severe failure to thrive at two years [27]. Holohan and colleagues brought together in 2016 a Canadian family and the original Saudi family to show telomere shortening, introducing the telomere maintenance component into the pathophysiology [28]. There followed the Japanese case of Dateki and colleagues (2018), with near-normal growth up to two years, hypospadias and a review of 14 patients, and the series of two Algerian sisters by Imbert-Bouteille and colleagues (2019), which added disproportionately mild microcephaly, stereotyped hand-wringing movements, anxiety and thickened skin of the hands and feet [13, 29]. Wojcik and colleagues (2019) diagnosed at 17 months the youngest patient to that date, described the first intronic splicing variant and showed the value of a formal developmental assessment [25]. Between 2020 and 2023 the syndrome was described in Italy, Iran, India (including sisters in their fourth and fifth decades), Oman (the largest single-centre series, with 12 patients from 8 families), Spain, Poland and China [23, 30–38].

1.4. Recent milestones (2023–2026)

Fauntleroy-Love and colleagues described in 2023 a North American boy with a deficient response to polysaccharide vaccine, periventricular nodular heterotopia and cerebral infarction, and proposed the first multisystem care guidance [15]. In 2025 there were published the first case of uniparental disomy of chromosome 4 [8], a homozygous missense variant with a functional study and a review of 51 patients [7], and a case with a single detected allele and a concomitant associated disease [14]. In 2026, Sharaf-Eldin and colleagues described seven Egyptian and Libyan patients with oro-dental anomalies and signs of humoral immunodeficiency in the boys [5], and Hassan and colleagues reported, in October, an Emirati boy with tetralogy of Fallot and a transcriptomic profile in fibroblasts [12]. The statement by Ambrose and colleagues that p.(Asp54Val) was the first missense variant described is not correct: He and colleagues had published in 2022 two Chinese sisters compound heterozygous for a nonsense variant and for the missense c.1141A>G p.(Lys381Glu) [7, 37]. The exact formulation is that p.(Asp54Val) was the first homozygous missense variant with a published functional study.

1.5. Nomenclature and entities with similar names

Alazami syndrome (OMIM 615071) should not be confused with Alazami–Yuan syndrome (ALYUS; OMIM 617126; ORPHA:694946), caused by variants in TAF6; the shared name derives from the same author, but the gene, the mechanism and the phenotype, which resembles Cornelia de Lange syndrome, are different [19, 20]. The first Caucasian patient is sometimes attributed to "Ling 2019"; the corresponding article is by Ling and Sorrentino, published in 2016 in the American Journal of Medical Genetics Part A [27]. The synonyms "microcephalic primordial dwarfism, Alazami type" and "síndrome Alazami" appear in Orphanet [1]. Orphanet classifies the disease among the rare bone diseases, by tradition of the classification of primordial dwarfisms, although skeletal involvement is mild and non-specific [1, 2].

2. Molecular Genetics and Pathophysiology

2.1. The LARP7 gene and protein

The LARP7 gene is located at 4q25, has 13 exons and is expressed throughout the body, with maximal expression in the brain; the MANE Select reference transcript is NM_016648.4, which encodes the protein NP_057732.2 [5–7]. The protein belongs to the family of La-related proteins (LARP). All LARPs have an N-terminal La motif (LaM) followed by a first RNA recognition motif (RRM1), a combination known as the "La module"; LARP7 additionally has a second C-terminal RRM motif (RRM2). The protein coordinates given in the 2026 series are 28–111 for LaM, 120–188 for RRM1 and 450–545 for RRM2 [5]. The La module recognises the uridine-rich 3′ end of RNA polymerase III transcripts, and it is through this end that LARP7 binds 7SK RNA [2, 7].

The protein was characterised in 2008 by He and colleagues, who named it PIP7S (P-TEFb interaction protein for 7SK stability) and assigned it 582 amino acids. In HeLa cells, almost all nuclear 7SK was associated with PIP7S; its knockdown by RNA interference lowered 7SK levels, prevented assembly of the 7SK snRNP and increased the P-TEFb-dependent expression of a reporter gene controlled by the long terminal repeat of human immunodeficiency virus type 1 (HIV-1). Binding required the La and RRM motifs of the protein and the 3′ uridine tail of 7SK, which indicates that LARP7 protects 7SK from degradation by 3′ exonucleases. Assays in yeast later showed that LARP7, like LARP4 and LARP6, has RNA chaperone activity centred on the RRM and the immediately downstream sequence, independent of binding to the uridine tail [4].

2.2. The 7SK snRNP complex and control of transcriptional elongation

7SK RNA is an abundant small nuclear RNA (snRNA) which, together with LARP7, the enzyme MEPCE and the HEXIM1 or HEXIM2 proteins, forms the 7SK ribonucleoprotein (7SK snRNP) [21]. This complex sequesters positive transcription elongation factor b (P-TEFb), a cyclin-dependent kinase required for activation of RNA polymerase II, in an inactive form. Without its release, P-TEFb does not phosphorylate RNA polymerase II, which remains paused near the promoter; 7SK thus acts as a brake on the transition to productive elongation at many genes [2, 7]. LARP7 is the constitutive chaperone of 7SK: it protects it from degradation, acts as a scaffold for the complex and remains bound to the RNA when P-TEFb is released [5, 7]. 7SK also takes part in the transcription of snRNA genes by RNA polymerase II through the little elongation complex and, according to the founding article, in a competing pathway of transcriptional regulation mediated by HMGA1 [7, 9].

In the founding article, the p.(Thr344LysfsTer9) variant abolished the protein on immunoblotting and reduced 7SK levels in patients' lymphoblastoid lines and fibroblasts; 7SK levels closely tracked those of LARP7 in the cell lines studied, and LARP7 showed ubiquitous expression in the mouse embryo [7, 9]. The reduction in LARP7 mRNA in patients' cells is compatible with nonsense-mediated decay. The causal relationship was tested in both directions: reintroduction of LARP7 by an expression vector restored 7SK levels in patients' fibroblasts, and silencing of LARP7 with two different interfering RNAs abolished 7SK in control fibroblasts; in situ hybridisation in 10.5-day mouse embryos showed expression in all tissues, most intense in the brain [3, 4, 9]. In the 2026 Emirati patient, LARP7 messenger ribonucleic acid (mRNA) in fibroblasts was about 15% of control and the full-length protein of about 75 kDa was not detected [12]. Loss of LARP7 function should therefore release P-TEFb from its brake and alter the expression of developmental gene programmes.

2.3. From molecular mechanism to phenotype: experimental models

The central paradox of the disease is that loss of an inhibitor of P-TEFb, which increases transcriptional elongation capacity, results in less growth. Three lines of research seek to explain it. In mouse embryonic stem cells, reduction of Larp7 did not significantly increase P-TEFb activity, but reduced the expression of Lin28, a positive regulator of organismal growth, through loss of the interaction with the poly(A) polymerase Star-PAP that stabilises Lin28 mRNA; the cells became primed for early differentiation, and the authors propose that an insufficient number of divisions before differentiation reduces body size [39]. In 2026, conditional ablation of Larp7 or Hexim1 in the mouse brain reduced the size and function of the hippocampal dentate gyrus in the neonatal period; increased P-TEFb activity reinforced the self-renewal programmes of transit-amplifying neuronal progenitors and limited neurogenesis, which reconciles excess P-TEFb with reduced growth of an organ [40]. The authors suggest the repurposing of P-TEFb inhibitors as a translational hypothesis; this is a preclinical result, without studies in humans [40]. A larp7−/− zebrafish model, described in a preprint without peer review, showed shorter body length, reduced interocular distance, delayed hatching, reduced locomotion, more anxiety-like behaviours and more aberrant splicing events [41].

2.4. U6 snRNA modification and splicing fidelity

Hasler and colleagues showed that LARP7 physically links the spliceosomal U6 snRNA to a subset of box C/D small nucleolar RNAs that guide the 2′-O-methylation of U6. Without LARP7, these modifications were severely compromised; global splicing was little affected, but disturbances of alternative splicing appeared, and cells from siblings with Alazami syndrome showed the same U6 methylation defect [10]. Altered splicing robustness is therefore a second plausible mechanism, which brings the syndrome close to other spliceosomal disorders associated with primordial dwarfism, such as RNU4atac-opathy [10, 11].

2.5. Telomeres, telomerase and the two-component model

Holohan and colleagues stably reduced LARP7 in HeLa cells with three interfering RNAs (protein reduction greater than 90%) and observed a 40–80% reduction in telomerase activity and progressive telomere shortening, with a decrease in full-length TERT mRNA and the −β isoform without reduction in total mRNA [28]. In lymphocytes from the original Saudi family and the Canadian family, telomeres were short in affected individuals, in carriers and also in non-carrier offspring of carriers, with a pattern suggestive of anticipation (initial difference of 560 base pairs between two generations). In the eight-year-old Canadian proband, flow cytometry with fluorescence in situ hybridisation showed telomere length below the 10th centile in all leucocytes and below the 1st centile in CD57+ NK cells, and single-telomere analysis gave values similar to those of a 28-year-old control [28]. The authors propose a model with a telomeric component acting in heterozygotes and a recessive developmental component; they acknowledge, however, that the mild anaemias observed in the patients may have an environmental cause and that no phenotype was severe enough to be attributed with confidence to a telomeropathy [28]. The transient erythroblastopenia described in two patients and the borderline anaemias of others keep this hypothesis open [12, 15].

2.6. Inheritance pattern and exceptional mechanisms

Inheritance is autosomal recessive in all sources. Most published patients are homozygous and born to consanguineous parents; in a review of 53 cases, 45 (85%) were homozygous, 8 (15%) compound heterozygous and 25 (47%) had consanguineous parents [14]. Penetrance is described as complete [7]. Heterozygotes are clinically normal: the parents of the Canadian family of Ambrose and colleagues, both carriers of p.(Asp54Val), had low expression of LARP7 mRNA (25.6% and 26% of normal) and were asymptomatic; the authors allow for epigenetic contributions in a family with consanguinity over two generations [7]. The telomere shortening in carriers described by Holohan and colleagues has no known clinical significance [28].

Three exceptional situations affect diagnosis and counselling. First, homozygosity may result from uniparental disomy: in a French boy of non-consanguineous parents, the variant was absent in the father, with confirmed paternity, and homozygosity analysis of the exome data revealed a 45 Mb region of loss of heterozygosity, confirmed by SNP microarray with four regions of loss of heterozygosity on chromosome 4, compatible with maternal uniparental disomy [8]. Second, in patients with a typical phenotype only a single allele may be detected: in the case of Thouqan and colleagues, the exome identified only a paternal variant, and the authors propose disomy, deletion, a deep intronic variant or mosaicism as explanations for the missing second allele, without having studied them [14]. That case does not constitute evidence of dominant inheritance. Third, homozygosity in parents without known consanguinity, as in the boy of Fauntleroy-Love and colleagues, may reflect remote consanguinity or uniparental disomy, hypotheses that the authors did not discuss [8, 15].

2.7. Variant spectrum and nomenclature

The 2025 review counted 24 different variants before the two most recent missense variants: 17 frameshift, 5 splicing and 2 large deletions [7]. About 80% of variants lie in exons 5 to 8 [5]. The common mechanism is the introduction of a premature termination codon with nonsense-mediated mRNA decay (NMD) and loss of function [5, 13]. The variants were normalised in VariantValidator against NM_016648.4 and the GRCh38 assembly; those that could not be normalised retain the published notation, with an indication to that effect [6].

Other variants cited in the review by Hassan and colleagues — among them c.325−2A>G and c.844_871del in the adult Indian sisters, c.1689+1G>C in Hosseini's Iranian family, the deletion c.802_1142+267del in Turkish siblings and c.502_552del in three Saudi sisters — were used only as written in that table [12, 43].

2.8. Missense variants and classification

Missense variants are rare and difficult to classify under the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), because the dominant mechanism is truncation. p.(Asp54Val), in the La motif, was first classified as a variant of uncertain significance (VUS) and reclassified as likely pathogenic after three-dimensional modelling with AlphaFold2 and quantitative PCR (qPCR) showing a significant reduction in LARP7 mRNA in the patients' blood [7]. The authors discuss possible mechanisms by which a missense variant reduces mRNA — alteration of exonic splicing enhancers or silencers, cryptic polyadenylation, altered mRNA structure or an indirect transcriptional effect — and acknowledge that they did not perform genome sequencing, so another undetected variant in cis was not excluded [7]. p.(Phe173Ser), in RRM1, affects a residue conserved in vertebrates and invertebrates, has a gnomAD frequency of 6.2 × 10⁻⁷ and scores of REVEL 0.73, MetaRNN 0.97 and CADD 29.2, and remained classified as a VUS [5]. p.(Lys381Glu), in trans with a nonsense variant in two Chinese sisters, predates both [37].

2.9. Genotype–phenotype correlations, variability and modifiers

There is no robust genotype–phenotype correlation: the core triad is common to all variant types, and severity and accessory manifestations vary even among patients with similar variants [5]. Intrafamilial variability is the rule: in an Algerian sibship, one sister had keratoconus and an atrial septal defect and the other seizures; in Iranian siblings, only one had seizures and unsteady gait; in Turkish siblings, one had pulmonary stenosis, diabetes mellitus and retinal changes, and the other seizures and lesser involvement [7]. Wojcik and colleagues hypothesised that the genotype composed of a truncating variant and an intronic splicing variant, possibly with residual protein production, contributed to the more favourable development of their patient, without demonstrating it [25]. Several reports document composite phenotypes due to a second genetic disease — OTOG-related deafness, osteo-oto-hepato-enteric syndrome due to UNC45A, phenylketonuria — which may be mistaken for phenotypic expansion [14, 30, 36].

2.10. Somatic alterations, allelic diseases and other genes of the 7SK complex

No allelic diseases of LARP7 have been described in humans in the sources consulted [2]. Outside the germline, LARP7 and the 7SK snRNP are dysregulated in tumours, with high expression described in gastrointestinal stromal tumours and in non-small cell lung cancer, and LARP7 behaves as a tumour suppressor in breast and gastric cancer cell lines [2, 32]. In the original description of the protein, its knockdown in a line of normal human mammary epithelial cells disorganised epithelial differentiation and caused P-TEFb-dependent malignant transformation [4]. An Italian man with Alazami syndrome had papillary thyroid carcinoma at 14 years, with the somatic variant BRAF V600E (historical notation, = NM_004333.6:c.1799T>A p.(Val600Glu)); the authors raised the hypothesis of tumour susceptibility, without demonstration [32]. A germline finding in LARP7 does not imply, with the available data, an established cancer predisposition [2]. The MEPCE subunit of the same complex is associated with a neurodevelopmental disorder with seizures, described in a boy with the de novo variant c.1552C>T p.(Arg518Ter): mRNA decay reduced MEPCE, LARP7 and 7SK, increased HEXIM1 and led to hyperphosphorylation of RNA polymerase II, effects reversed in vitro by flavopiridol, a P-TEFb inhibitor, and by re-expression of MEPCE [21]. A bioinformatic co-expression analysis suggests a functional relationship between LARP7 and dyskerin (DKC1), without experimental validation [5].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what they measure

Clinical knowledge rests on case reports, small family series and cumulative literature reviews, all without prospective follow-up. The main reviews are those of Dateki and colleagues (14 patients published up to 2018), Ambrose and colleagues (51 patients up to 2025), Thouqan and colleagues (53 patients up to 2025) and Hassan and colleagues (60 patients up to 2026, including their own case) [7, 12–14]. The reviews overlap, because they recount the same patients, and differ in denominator: Dateki and Thouqan count only the patients in whom the sign was described, whereas Hassan includes in the denominator patients without information, which underestimates frequencies [12]. Orphanet frequencies are categories annotated from about ten cases or families and are not cohort percentages [1]. No series systematically distinguishes natural history from course under intervention, because there is no disease-modifying treatment and the interventions described are rehabilitative and supportive.

The table includes only signs with data in at least two sources; ASD denotes atrial septal defect. Differences between columns mainly reflect the counting method and not a change in phenotype over time.

3.2. Growth

Growth restriction is the most constant somatic sign, but its onset and severity vary. Some patients have documented IUGR — the Canadian sisters of Ambrose and colleagues were born with weight below the 3rd centile after pregnancies with pre-eclampsia, and the boy of Thouqan and colleagues was born at 36 weeks weighing 1460 g (−2.89 SD), 42 cm long (−2.94 SD) and with a head circumference (HC) of 28 cm (−2.87 SD) [7, 14]. In others, prenatal growth is normal: Ambrose's Canadian boy was born on the 50th centile, Dateki's Japanese boy was born at 38 weeks measuring 46 cm (−1.3 SD) and weighing 2.44 kg (−1.1 SD) and measured 80.6 cm (−1.14 SD) at two years, and one of the adult Indian sisters did not have short stature [7, 13, 23]. In the founding family, all affected individuals had growth parameters below −3.5 SD, and the first patient of European ancestry had a height of −4 SD at two years, with failure to thrive [3, 27]. After birth, height ranged from −2.5 to −10.5 SD in the 2018 review, with examples of 129 cm at 22 years (−10.5 SD) and 138 cm at 20 years (−9.7 SD) [13]. In the Egyptian and Libyan series of seven patients aged 2 to 15 years, height ranged from −2.9 to −6.4 SD and weight from −1.7 to −5.7 SD, with onset recognised between 6 months and the first year [5]. Infant failure to thrive is often associated with severe feeding difficulties: the patient of Fauntleroy-Love and colleagues had a length of −4.91 SD and a weight of −3.03 SD at 20 months, with severe malnutrition and oropharyngeal dysphagia that led to gastrostomy [15]. Random growth hormone (GH) and insulin-like growth factor 1 (IGF-1) measurements were normal in the infants in whom they were performed [15, 25].

3.3. Microcephaly

Microcephaly is frequent but usually mild and disproportionately less marked than the restriction of stature, unlike MOPD II and Seckel syndrome [1, 29]. In the review by Imbert-Bouteille and colleagues, which added 15 previously published patients to the two Algerian sisters, 11 of 14 patients with data had disproportionately mild microcephaly, with stature more affected than HC [3, 29]. In the 2026 series, 4 of 7 patients had microcephaly, with HC between −1.1 and −3.67 SD [5]; the infant of Wojcik and colleagues had an HC on the 49th centile at 5 months and on the 80th centile at 2 years [25]; the adult Indian sisters were not microcephalic [23]. At the severe end, the boy of Thouqan and colleagues had an HC of −9.03 SD at 11 months, in a picture with a concomitant second genetic disease [14].

3.4. Facies and skin

The facies is the main element of clinical recognition: triangular face, sometimes long, with a high or prominent forehead, deep-set eyes, short or narrow palpebral fissures, sparse eyebrows, malar and midface hypoplasia, low-set ears, broad nasal root with a bulbous tip and hypoplastic alae, short philtrum, wide mouth with thick lips and widely spaced teeth [1, 13]. In the 2026 series, all seven patients had a pointed and prominent chin, deep-set eyes, a broad nasal root, hypoplastic alae nasi, low-set ears and a high forehead; four had a long face, and macrostomia appeared in only two [5]. Imbert-Bouteille and colleagues described thickened skin of the hands and feet, and Orphanet annotates cutis marmorata and thickened skin as frequent [1, 29]. The frequency of this sign differs greatly between reviews: 11 of 14 in that of Imbert-Bouteille and colleagues, 4 of 12 in that of Dateki and colleagues and 9 of 60 in that of Hassan and colleagues, who count patients without information in the denominator; the discrepancy mainly reflects the way the sign is recorded in retrospective reports [3, 12, 13]. In the founding family, the constant facial features were malar hypoplasia, deep-set eyes, a broad nose, a short philtrum and macrostomia [3, 9]. There are isolated reports of blue-grey sclerae, hyperkeratosis, a café-au-lait spot and truncal obesity with acne [12, 13].

3.5. Neurodevelopment, language and behaviour

All published patients have global developmental delay and ID [14]. The degree is usually moderate to severe: in the 2026 series, ID was severe in 2 patients (intelligence quotient, IQ, 33 and 34) and moderate in 5 (IQ 41–49), speech was absent in one, limited to letters in another and to a few words in the rest, and independent walking appeared between 1 year 4 months and 3 years 4 months [5]. In the Imbert-Bouteille family, the patients aged 22 and 26 years had no words [25]. At the other extreme, the Japanese boy had a full-scale IQ of 67 at two years and the infant of Wojcik and colleagues walked at 14 months, with borderline cognition on the Bayley-III scale at 22 months (equivalent to 15 months), language well below expectations (receptive at 13 months and expressive at 7 months) and borderline adaptive functioning on the Vineland-3 scale [13, 25]. The Canadian patients of Ambrose and colleagues acquired motor milestones and early language in the first year to year and a half and only then showed global delay, a pattern worth recording in the history [7].

Behaviour is part of the phenotype. Anxiety, including to loud noises, sensory hypersensitivity, aggressiveness, hyperactivity, obsessive-compulsive disorder, repetitive mannerisms and stereotyped hand-wringing movements are described [5, 7, 25, 29]. In the 2019 review, hand-wringing and severe anxiety each appeared in 2 of 5 patients with data [3, 29]. The North American patient of Ling and Sorrentino had, at two years, involuntary hand movements, poor language, precarious balance with a broad-based gait, hypersensitivity to touch and sound and anxiety reported by the parents, with normal brain imaging [3, 27]. In the 2026 series, 6 of 7 patients had autistic traits, 4 nervousness, 3 hyperactivity and 2 insomnia; Ambrose's Canadian boy has a diagnosis of autism spectrum disorder, attention deficit hyperactivity disorder and anxiety [5, 7]. Orphanet annotates self-injury and alterations of eating behaviour and sleep [1]. The infant of Wojcik and colleagues, sociable and with preserved attachment, communicated through gestures, some signs and eye contact [25].

3.6. Central nervous system, seizures and stroke

Brain magnetic resonance imaging (MRI) may be normal. The findings described include a thin corpus callosum (in the seven patients of the 2026 series and in Wojcik's infant), a disorganised folial pattern of the cerebellar hemispheres, unilateral insular and anterior frontal cortical thickening in the founding family, periventricular white matter hyperintensity, agenesis of the corpus callosum with absent septum pellucidum, Chiari type 1 malformation with venous angioma, mildly delayed myelination and periventricular nodular heterotopia [5, 15, 25]. These attributions to specific patients come from the reviews of Sharaf-Eldin and of Fauntleroy-Love and colleagues. In the founding family, MRI was performed in two patients: one with almost no abnormalities and the other with mild unilateral insular and anterior frontal cortical thickening [3, 9]. Seizures occur in about 10% of published patients, including isolated febrile seizures, and did not occur in any of the seven patients of the 2026 series [5, 7]. The first published stroke was a left anterior frontal infarct during Haemophilus influenzae meningitis in a boy heterozygous for factor V Leiden and with elevated lipoprotein(a), a combination of causes that the authors consider contributory [15]. Tone may be reduced axially, increased in the limbs or associated with hyperreflexia [5, 7].

3.7. Heart

About one third of published patients have heart disease, according to the 2025 review, which gives no explicit denominator; the 2026 table counts 13 septal defects in 60 patients (21%), with the underestimation already mentioned [7, 12]. The defects described are atrial septal defect, ventricular septal defect, valvular and pulmonary artery stenosis, interventricular septal thickening, left ventricular non-compaction, non-stenotic bicommissural aortic valve with a dilated left ventricle and, in an Emirati boy, classic tetralogy of Fallot with valvular, subvalvular and supravalvular pulmonary stenosis and ostial stenosis of the left pulmonary artery [7, 12, 28]. In the 2026 series the cardiac examination was normal in all seven patients [5]. In experimental models, loss of LARP7 increases endothelial-to-mesenchymal transition in the endocardial cushions, a plausible mechanism for the valvular and septal defects [15].

3.8. Skeleton and limbs

Skeletal involvement is mild and non-specific, not a skeletal dysplasia [2]. Scoliosis or kyphoscoliosis, lumbar lordosis and sacral asymmetry, contractures, epiphyseal changes of the proximal phalanges, advanced bone age (+2 SD in an infant), a large calvarium, increased cortical thickness, tall vertebrae with small discs, slender long bones, a short Achilles tendon, arachnodactyly (5 of 7 patients in the 2026 series), clinodactyly, adducted thumb, clubfoot, syndactyly and overlapping toes are described [5, 7, 13, 15, 25, 31]. Scoliosis was frequent in the literature (4 of 13 patients with data in the 2019 review) and absent in the Egyptian and Libyan series [3, 5, 29]. In the founding family, scoliosis and mild epiphyseal changes of the proximal phalanges were inconstant, without a defined dysplasia and with bone age consistent with chronological age [3, 9].

3.9. Oro-dental region

The 2026 series is the first to examine the oral cavity systematically: prominent premaxilla and thin upper lip in 7 of 7 patients, high-arched palate in 6, anterior open bite in 5 (the article's discussion mentions six, but the table, used here, shows five), enamel hypoplasia or hypocalcification in 5, retrognathia in one and widely spaced and malpositioned teeth in two [5]. Dental crowding was described in the Indian sisters, and a 2025 report describes the multidisciplinary dental management of a patient with malocclusion [23, 44]. The role of LARP7 in enamel formation is not known [5].

3.10. Kidney and genital tract

The genitourinary anomalies described include small kidneys, ectopic kidney, bilateral hydronephrosis, pelviureteric junction obstruction, ureteric lithiasis, renal artery stenosis and prehypertension [5, 12, 15, 28]. A 2026 report, read only in its title, presents nephrolithiasis as a new finding [45]. In boys, cryptorchidism, micropenis, hypospadias and buried penis [5, 13, 15]. In the Omani series of 12 patients, genitourinary anomalies were one of the expansions of the phenotype [34].

3.11. Immunity and haematology

Humoral immunodeficiency is the most recently proposed manifestation. Before 2026 two boys had been described: one with recurrent otitis and respiratory infections and the boy of Fauntleroy-Love and colleagues, with more than ten episodes of otitis, H. influenzae meningitis and no adequate response to the 23-valent pneumococcal polysaccharide vaccine four weeks after administration, with normal lymphocyte subsets, immunoglobulins, response to tetanus toxoid and total haemolytic complement (CH50) [5, 15]. In the 2026 series, the three boys had recurrent ear, skin or respiratory infections and met 3, 4 and 6 of the ten warning signs of primary immunodeficiency, whereas the four girls met 0 or 1; lymphocyte counts were normal, apart from mild CD8 changes in three patients, and serum immunoglobulins were normal [5]. After one dose of 23-valent polysaccharide vaccine, with serology before and one month after, the girl tested responded and the boy had no detectable response, which constitutes a functional defect of antibody production against polysaccharides [5]. The authors propose that the deficiency is an under-recognised and possibly male-predominant feature, a hypothesis resting on five boys with warning signs and two with a proven deficient response [5, 15].

On the haematological side, transient erythroblastopenia of childhood was described in two patients (one with haemoglobin of 6.8 g/dL), microcytic anaemia in several members of the Saudi family and borderline anaemia in the Canadian boy, without signs of dyskeratosis congenita [12, 15, 28].

3.12. Sense organs

Hearing loss, conductive or sensorineural, and recurrent otitis media have been described in fewer than ten patients, and two of Ambrose's three Canadian patients had hearing loss, one with a hearing aid [7]. Profound sensorineural deafness may result from a second genetic disease, such as the OTOG variant in the Italian patient of Palumbo and colleagues [30]. Ocular anomalies include strabismus, keratoconus, unilateral buphthalmos, microphthalmia with microcornea, myopia, bilateral cataracts and retinal changes [7, 12, 23]. The Omani series added ophthalmological anomalies to the phenotype [34].

3.13. Digestive tract, feeding and sleep

Infant feeding difficulties — aspiration, oropharyngeal dysphagia, need for a nasogastric tube or gastrostomy — have been described in several patients [12, 15, 25]. Gastro-oesophageal reflux disease and constipation appear in isolated reports [7]. Obstructive sleep apnoea was treated by adenoidectomy and supraglottoplasty at 11 months in one patient, and sleep fragmentation was documented by polysomnography in another [7, 15].

3.14. Endocrine system

Hyperthyroidism has been described in two patients, one from the Omani series and a Jordanian girl, papillary thyroid carcinoma in an Italian man and, in a 2026 conference abstract read only in its title, hypothyroidism [12, 32, 42, 46]. In the Emirati boy's family there was thyroid carcinoma in two relatives, with no established causal relationship [12]. Diabetes mellitus was described in a Turkish sibling and hypercholesterolaemia in an Iranian patient [7, 12].

3.15. Adulthood and natural history

Life expectancy is not known and patients reach at least young adulthood [5]. The oldest published are the Indian sisters in their fourth and fifth decades (42 and 44 years according to the 2026 table), without microcephaly and one of them without short stature, and three Saudi sisters aged between 20 and 26 years [12, 23]. The adult patients of the Imbert-Bouteille family had no verbal language [25]. Most need variable help with daily activities; autonomy depends on the degree of ID, language delay and motor deficit [5]. There are no longitudinal data on the course of scoliosis, renal function, heart disease or immunity in adulthood in the sources consulted.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Alazami syndrome is rarely suspected before genetic testing: all published patients were diagnosed by next-generation sequencing, as a rule by exome, and not by targeted clinical suspicion, because the disease is rare and the phenotype overlaps with that of many neurodevelopmental disorders [5, 34]. Clinical suspicion nevertheless has value in guiding analysis of genomic data and in recognising the associated manifestations. The combination that should lead to consideration of the syndrome is growth restriction of prenatal or postnatal onset with global developmental delay and a triangular facies with a high forehead, deep-set eyes, malar hypoplasia, broad nose, short philtrum and wide mouth, especially when microcephaly is mild relative to the stature deficit [5, 13, 29].

4.2. Warning and emergency signs in a diagnosed patient

In a patient with an established diagnosis, some signs require targeted and sometimes urgent assessment. Recurrent ear, skin or respiratory infections, an invasive bacterial infection or a weak vaccine response justify study of humoral immunity, particularly in boys [5, 15]. An acute focal neurological deficit, especially in the context of meningitis, should be treated as possible stroke, and parents should know the signs of stroke and seizures [15]. Coughing during meals, aspiration pneumonias or weight loss suggest dysphagia; snoring, respiratory pauses and restless sleep suggest obstructive sleep apnoea, which has implications for sedation and anaesthesia [1, 15]. Marked pallor may correspond to transient erythroblastopenia [15]. Loss of acquired skills has not been described in the sources consulted (the Canadian boy of Holohan and colleagues had delay without regression) and justifies looking for another cause [28].

4.3. Newborn screening

There is no newborn screening for Alazami syndrome. Coexistence with phenylketonuria in a Polish boy treated since newborn screening, with good metabolic control and unexplained ID, shows that a diagnosis obtained through screening does not exclude a second monogenic disease when the phenotype does not match what is expected [36].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria or diagnostic consensus; the diagnosis is molecular and requires biallelic pathogenic or likely pathogenic variants in LARP7 in a patient with a compatible phenotype [1, 2]. There are no specific biochemical biomarkers. Measurements of GH, IGF-1, thyroid function, prolactin and cortisol were normal in the infants in whom they were performed and serve to exclude other causes of short stature [15, 25].

5.2. Clinical assessment and initial investigation

The international consensus on children born small for gestational age (SGA) recommends, in an SGA child with persistent short stature, endocrine assessment with thyroxine, thyroid-stimulating hormone and IGF-1 (with or without IGFBP-3), and reserves the GH stimulation test for suspected deficiency; it also recommends referral to clinical genetics when there are dysmorphic features, malformations, microcephaly, developmental delay, ID or signs of skeletal dysplasia (strength A+++), and proposing genetic testing when short stature persists without an identified cause (A++) [16]. The assessment of a patient with suspected Alazami syndrome also includes serial measurement of growth and HC on reference charts, developmental and cognitive assessment, echocardiogram and electrocardiogram, spinal radiograph if scoliosis is suspected, brain MRI, oro-dental examination and, if the infectious history justifies it, immunoglobulins, lymphocyte subsets and antibody responses to protein and polysaccharide antigens [2, 15]. There is no biochemical biomarker: in the founding family, plasma amino acids, acylcarnitines, urinary organic acids, very-long-chain fatty acids, full blood count and renal and bone profiles were normal, so metabolic investigation serves only to exclude other diagnoses [3, 9].

5.3. Genetic tests and order of use

The first-line test is exome sequencing, preferably as a trio, or an extended ID, autism or syndromic short stature panel that includes LARP7 [5, 7]. In the published series, trio exome sequencing enabled diagnosis at 17 months and excluded other causes suggested clinically, such as Smith–Lemli–Opitz syndrome [25, 31]. For the group of primordial dwarfisms, GeneReviews considers the multigene panel the route most likely to identify the cause while limiting VUS, with content and sensitivity varying between laboratories [11]. Chromosomal microarray, often requested first in the presence of ID, was normal in the patients with Alazami syndrome in whom it was performed, and does not detect point variants [7, 25].

5.4. Limitations of the tests

There is no published estimate of the clinical sensitivity of exome sequencing or panels for the syndrome. The documented mechanisms that may escape conventional analysis are large intragenic deletions (2 of the 24 variants known in 2025, such as c.802_1142+267del), which require CNV analysis or multiplex ligation-dependent probe amplification (MLPA); intronic splicing variants outside the canonical positions, such as c.646+5G>C; uniparental disomy, detectable by analysis of regions of homozygosity in exome data or by SNP microarray; and the unidentified second allele, as in the case with a single variant [7, 8, 12, 14, 25]. A negative result on a panel without CNV analysis does not exclude the diagnosis. Faced with a single truncating variant in LARP7 in a patient with a typical phenotype, the next step is to search for the second allele by CNV analysis, SNP microarray, MLPA, genome sequencing and, where available, RNA studies [8, 14]. Homozygosity in a patient of non-consanguineous parents justifies parental testing to confirm biparental origin [8].

5.5. Variants of uncertain significance and functional evidence

Missense variants require additional evidence. In the case of p.(Asp54Val), reclassification from VUS to likely pathogenic relied on segregation in two homozygous sisters with heterozygous parents, on structural modelling and on qPCR of LARP7 mRNA in blood, which showed a significant reduction in homozygotes compared with controls [7]. Expression studies in fibroblasts (mRNA and immunoblotting of the protein of about 75 kDa) are another route of functional evidence [9, 12]. p.(Phe173Ser) remains a VUS, despite concordant computational predictions, for lack of a functional study [5].

5.6. Report content

The report should state the gene, the transcript with version (NM_016648.4), the HGVS notation at DNA and protein level, the zygosity, the ACMG/AMP class with the criteria applied and the results of parental segregation. The criteria most used in recent series were PVS1 (null variant in a gene in which loss of function causes disease), PM2 (absence or extreme rarity in population databases) and PP3 (concordant computational predictions) [5]. Variants published on other transcripts, such as NM_001267039 or NM_015454, should be converted to the MANE transcript for comparison with the literature [6, 13, 30].

5.7. Prenatal and preimplantation diagnosis

After identification of the two familial variants, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing for monogenic disease (PGT-M) are possible; a PGT-M programme using Sanger sequencing in Iraqi Kurdistan included Alazami syndrome as the indication in one cycle, among 47 cycles and 295 embryos studied [47]. Ultrasound does not allow a specific diagnosis: IUGR, when present, appears in the third trimester, and many patients have normal prenatal growth [7, 13].

5.8. Proposed algorithm

This algorithm is a synthesis of the practices described in the series and in the SGA consensus, not a validated recommendation.

6. Differential Diagnosis

6.1. Logic of the differential diagnosis

The differential diagnosis is organised into three groups: the microcephalic primordial dwarfisms, in which growth restriction and microcephaly are extreme (both below −4 SD in the GeneReviews definition); syndromes of short stature of prenatal onset with ID and facial dysmorphism; and entities with a similar name or mechanism [11, 16, 22]. In Alazami syndrome, three features help separate it from the first group: microcephaly is mild or absent relative to the stature deficit; ID is usually moderate to severe, whereas in MOPD II intelligence is normal or only slightly reduced; and the skeleton shows mild, non-specific changes, without the dysplasia of MOPD I and II [2, 29, 48]. LARP7 does not appear in the differential diagnosis table of the GeneReviews chapter on MOPD II nor in the tables of monogenic disorders of the SGA consensus, which reinforces the need to use broad panels or exome sequencing [11, 16].

6.2. Differential diagnosis table

6.3. Main differential diagnoses in prose

MOPD II is the most common microcephalic primordial dwarfism and the classic differential diagnosis. The distinction is mainly quantitative and cognitive: in MOPD II birth weight is around −4 SD, height and HC reach −8 to −10 SD and adult height remains below 100 cm, but intelligence is normal or only slightly reduced; there is a risk of moyamoya and cerebral aneurysms and of insulin resistance [22, 48]. In Alazami syndrome the stature restriction may be just as severe, but microcephaly is proportionally less marked and ID is the rule [13, 29]. MOPD I/III, the severe expression of RNU4atac-opathy, is distinguished by severe brain malformation, contractures, skeletal dysplasia and early mortality, and shares with Alazami syndrome the disturbance of a spliceosomal snRNA [10, 48]. Seckel syndrome has disproportionate microcephaly and a facial profile with a prominent nose and sloping forehead, different from the triangular face with a broad nose [22, 48]. Meier–Gorlin syndrome is distinguished by the triad of microtia, patellar hypoplasia and short stature, with usually normal intelligence [22].

Among the short-stature syndromes with ID, Floating-Harbor syndrome is the closest facial differential, because of the triangular face, deep-set eyes, bulbous nose and short philtrum; the autosomal dominant inheritance pattern helps to separate it [16]. Smith–Lemli–Opitz syndrome was the first clinical hypothesis in two Italian siblings with toe syndactyly who turned out to have Alazami syndrome; measurement of 7-dehydrocholesterol separates the two entities [31]. In the DNA repair disorders (Bloom, Fanconi anaemia, Nijmegen, LIG4, XRCC4), the differential diagnosis has an immediate therapeutic consequence, because the SGA consensus advises against or contraindicates GH in these cancer-predisposing diseases [16].

6.4. Composite phenotypes

In a patient with confirmed Alazami syndrome, atypical findings may result from a second genetic disease, especially in consanguineous families: profound deafness due to OTOG [30], osteo-oto-hepato-enteric syndrome due to UNC45A with cholestasis, diarrhoea and deafness [14], phenylketonuria [36], and carrier states or risk factors such as heterozygosity for G6PC and factor V Leiden [15]. In the case of Thouqan and colleagues, the authors themselves state that the parents and a healthy sister carry the UNC45A variants, so the causality of that second disease is not demonstrated in the article [14]. Assessment of each new finding should consider this possibility before attributing it to LARP7.

7. Treatments and Risk Management Strategies

7.1. General principles and level of evidence

There is no disease-modifying treatment, nor any clinical trial, formal consensus or GeneReviews chapter; the available evidence is that of case reports and case series [2, 5]. Management is multidisciplinary, guided by each patient's manifestations and maintained throughout life [5]. The only structured care proposal is the table of guidance published by Fauntleroy-Love and colleagues in 2023, prepared by a group of authors from one case and a literature review; it has the value of expert opinion and not of a guideline [15]. Subsequent series added the recommendation of a baseline echocardiogram in all patients and of systematic immunological assessment [5, 12]. The approach to growth relies, by declared extrapolation, on the 2023 international consensus on children born SGA, which does not mention Alazami syndrome [16]. The drugs mentioned below have neither an indication nor a study in the syndrome; doses come from the guidelines for the analogous condition or from the official labels, with the source and the extrapolation made explicit.

7.2. Nutrition and feeding

Infant failure to thrive is often associated with feeding difficulties, aspiration and oropharyngeal dysphagia. The 2023 proposal recommends monitoring feeding, requesting a swallowing study in the presence of poor weight gain or suspected aspiration, looking for signs of malnutrition and involving a dietitian [15]. The patients described needed thickened formula, prolonged nasogastric tube feeding or gastrostomy [12, 15, 25]. In MOPD II, GeneReviews advises against excessive nutritional supplementation of the infant, because it does not normalise growth in a restriction of primordial origin; in the sources consulted there are no equivalent data for Alazami syndrome, and the principle applies only by analogy, while maintaining the aim of correcting documented malnutrition [11].

7.3. Growth hormone (somatropin)

No patient with Alazami syndrome treated with growth hormone was found in the sources consulted; the absence of a study does not demonstrate inefficacy. In the infants studied, random GH and IGF-1 were normal, which does not suggest GH deficiency [15, 25]. A 2024 Jordanian report mentions "growth monitoring and therapy" with improvement in height, weight and communication within three months, but does not identify the treatment in the accessible text and has no control, so it does not constitute evidence of efficacy [42].

Three sets of arguments should be weighed before proposing somatropin. In favour of an individual trial: many patients are born SGA and maintain persistent short stature, the situation in which the SGA consensus recommends GH at 3–4 years once other causes have been excluded (strength A+++) [16]. Against: the classic criteria for treating SGA children exclude dysmorphic syndromes, with the exception of Silver–Russell syndrome; in MOPD II, a primordial dwarfism of another mechanism, GH without demonstrated deficiency was not useful and may contribute to morbidity; and the consensus advises against GH in genetic diseases with cancer predisposition, such as the chromosome breakage and DNA repair syndromes (A+++) [11, 16, 48]. Specific uncertainty: LARP7 behaves as a tumour suppressor in cell lines and there is one papillary thyroid carcinoma in a patient, without demonstration of germline cancer predisposition [2, 32]. A treatment decision is therefore individual, shared with the family and led by paediatric endocrinology, with the response thresholds defined before starting.

When GH is proposed, the reference dose is that of the SGA consensus; the FDA and EMA labels are cited for comparison. The table summarises the three sources.

[16, 49, 50]

Monitoring under GH, according to the consensus, should not adjust the dose on IGF-1 alone; IGF-1 is measured at 3–6 months and then annually, free thyroxine and thyroid-stimulating hormone annually, and bone age at around 8 years and from puberty onwards, not every year in the prepubertal phase [16]. Treatment is stopped when growth is less than 1 cm in 6 months with closed epiphyses, or for lack of adherence or response; the European SmPC adds discontinuation after the first year if height velocity is below +1 SD and when velocity is below 2 cm/year with a bone age above 14 years in girls or 16 years in boys [16, 50]. Somatropin is contraindicated in the presence of any tumour activity and with closed epiphyses, and the SmPC mentions an increased risk of a second neoplasm in treated cancer survivors [50]. In a patient with Alazami syndrome on GH, clinical surveillance of the thyroid is justified by the occurrence of thyroid disease in the syndrome [12, 32]. The consensus also proposes, in SGA children on GH with a predicted adult height below −2.5 SD at the onset of puberty, the addition of a gonadotrophin-releasing hormone analogue for two years, with a mean gain of 6.6 cm (A++); this combination has not been studied in Alazami syndrome [16].

7.4. Humoral immunodeficiency

Immunological assessment should be performed in the presence of recurrent infections, invasive bacterial infection or a weak vaccine response, and Sharaf-Eldin and colleagues propose that it be done systematically in all new patients [5]. The 2023 proposal includes a full blood count with differential, lymphocyte subsets with T and B phenotyping, IgG, IgA, IgM and IgE, and antibody titres against tetanus and pneumococcus, with surveillance of infections and vaccine response [15]. The patients described had normal total immunoglobulins, so the deficiency is revealed only by the response to polysaccharide antigens [5, 15]. The schedule of conjugate vaccines against H. influenzae type b and pneumococcus should be complete: the boy who had meningitis had received only two of the four doses of each series [15].

The polysaccharide vaccine response test uses the 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23®), approved by the FDA for people aged 50 years or older and for people aged 2 years or older at increased risk of pneumococcal disease, as a single 0.5 mL dose by the intramuscular or subcutaneous route; it is contraindicated after anaphylaxis to any of its components [51]. This diagnostic use is distinct from prevention: in at-risk children and adolescents, the recommendation of the HAS (French National Authority for Health) validated on 23 July 2026 provides for a single dose of PCV20 from 15 months to 18 years and abandons PPSV23, whereas the CDC recommends PCV15 or PCV20 from 2 to 18 years, with PCV20 or PPSV23 at least 8 weeks after a complete series without PCV20 [52, 53]. In the series, serology was collected before and four weeks to one month after the vaccine [5, 15]. The European SmPC of Hizentra® defines proven specific antibody failure as failure to mount at least a two-fold rise in IgG titres against pneumococcal polysaccharide and polypeptide antigens [54].

Normal human immunoglobulin by the subcutaneous route (SCIg) was started in a single patient with Alazami syndrome, at 24 months, for suspected specific antibody deficiency with invasive infection; the dose was not published and follow-up was lost [15]. There is no guideline with a dose for this condition in the sources consulted, so the reference is the labels for primary immunodeficiencies with impaired antibody production, by declared extrapolation.

[54, 55]

The first infusion in a patient without previous immunoglobulin requires monitoring during the infusion and for the following hour [54]. The thromboembolism warning has concrete relevance: the only patient with Alazami syndrome treated with SCIg had had a cerebral infarct and was heterozygous for factor V Leiden, with elevated lipoprotein(a) [15, 54].

7.5. Sleep

Sleep disturbance and obstructive apnoea are described as occasional [1, 7]. In the presence of snoring, restless sleep or respiratory pauses, the 2023 proposal recommends polysomnography; obstructive apnoea was treated in one patient with adenoidectomy and supraglottoplasty [15]. For insomnia that persists after sleep hygiene measures, prolonged-release melatonin Slenyto® was authorised in the EU on 20 September 2018 for children and adolescents aged 2 to 18 years with autism spectrum disorder and/or Smith–Magenis syndrome, and the Commission decision of 26 August 2024 extended the indication to neurogenetic disorders with aberrant diurnal melatonin secretion or nocturnal awakenings (that of 17 March 2025 added insomnia from 6 to 17 years with ADHD); Alazami syndrome is not included by name and its use is a declared extrapolation, justified by the frequency of autistic traits and insomnia [5, 56]. The starting dose is 2 mg once daily, 0.5 to 1 hour before bedtime, with or after food, increasing to 5 mg if the response is insufficient, up to a maximum of 10 mg; the 1 mg and 5 mg tablets are swallowed whole, without breaking or chewing, and may be mixed with yoghurt or juice to make them easier to take [56]. The effect is assessed at 3 months and treatment is reassessed at least every 6 months; frequent adverse effects are mood changes, aggressiveness, irritability, somnolence, headache and sudden onset of sleep [56].

7.6. Neurology and stroke

Seizures occur in about 10% of patients and include isolated febrile seizures that required no treatment [7]. The 2023 proposal recommends teaching the family the signs of seizures and stroke and requesting an electroencephalogram when suspected [15]. The sources consulted do not describe antiseizure treatment of patients with Alazami syndrome or differences in response, so the choice follows the classification of each patient's epilepsy. In paediatric stroke, the authors recommend the same prothrombotic work-up as in the general population, which in their patient revealed factor V Leiden and elevated lipoprotein(a) [15].

7.7. Development, education and behaviour

Developmental intervention is the measure with the greatest foreseeable impact on autonomy. Wojcik and colleagues advocate a formal developmental assessment soon after diagnosis, with standardised instruments (Bayley-III and Vineland-3 in their patient), which identified a profile with expressive language well below the other domains and guided the continuation of early intervention, occupational therapy, intensification of speech therapy, integration into a play group and preparation for the transition to preschool education at 3 years [25]. The 2023 proposal recommends speech therapy, occupational therapy and physiotherapy according to need [15]. Speech therapy, educational guidance and neuropsychiatric support are described as useful, without a comparative study [5]. The three Canadian patients attend adapted school programmes with an assistant [7]. In the infant of Wojcik and colleagues, communication was through gestures and some signs, which supports the early use of augmentative forms of communication [25]. Anxiety, hyperactivity, stereotypies, self-injury and autistic traits justify child psychiatric assessment; autism spectrum disorder and attention deficit hyperactivity disorder were diagnosed in one patient [5, 7]. The sources consulted do not describe the response to psychotropic drugs in this syndrome.

7.8. Other areas of care

7.9. Regulatory status

There is no authorised medicine nor any application for authorisation for Alazami syndrome, and ClinicalTrials.gov had, on 28 October 2026, no registered study with the terms "Alazami" or "LARP7" [57]. The drugs of possible use are supportive and the table compares the framework of their indications.

[49–51, 54–56]

7.10. Available evidence on interventions

[5, 15, 25, 42, 57]

None of these reports allows efficacy to be estimated: they are observations of one or two patients, without a comparison group or prolonged follow-up, and the only patient treated with SCIg has no published outcomes. The care recommendations derive from expert opinion and extrapolation from other conditions, and not from intervention studies.

7.11. Developments in the last 6–12 months

[5, 7, 8, 12, 14, 40, 41, 45, 46]

None of these developments has a therapeutic translation: there is no human study of P-TEFb inhibitors in this syndrome, and flavopiridol only reversed expression changes in vitro in cells with loss of MEPCE [21, 40].

7.12. Agents and circumstances to avoid or to use with caution

Somatropin should not be started without assessment by paediatric endocrinology and discussion of the theoretical cancer risk, and it is contraindicated in the presence of tumour activity [16, 50]. Excessive nutritional supplementation of the infant does not normalise growth in the primordial dwarfisms [11]. Immunoglobulin requires weighing of the thrombotic risk in patients with stroke or thrombophilia [15, 54]. Melatonin should be used with caution in renal impairment and is not recommended in hepatic impairment [56].

7.13. Anaesthesia, sedation and the perioperative period

There are no reports of specific anaesthetic complications in the sources consulted. Several known features of the syndrome should nevertheless be part of the pre-anaesthetic assessment: obstructive sleep apnoea, the retrognathia or micrognathia and maxillary hypoplasia described in some patients, congenital heart disease, low weight for age and swallowing difficulties with a risk of aspiration [5, 12, 14, 15]. A recent echocardiogram should be available before elective surgery, consistent with the recommendation of a baseline echocardiogram [12].

7.14. Pregnancy, lactation and adult life

The sources consulted do not describe pregnancies in women with Alazami syndrome. Two adult Indian sisters underwent hysterectomy, without the indication being available in the text consulted [12]. In adult life the needs for support in daily activities, and for surveillance of the associated manifestations, persist [5]. The transition from paediatric to adult care has not been studied in this syndrome; the list of active problems (heart disease, scoliosis, kidney, immunity, thyroid) should accompany the patient.

7.15. Guidelines and divergences

[5, 12, 15, 16, 49, 50]

ERN ITHACA has no specific guideline for Alazami syndrome [17].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In the usual situation, both parents of a patient are asymptomatic heterozygotes, and each pregnancy has a 25% risk of an affected child, 50% of a heterozygous child and 25% of a child without the variant [1, 2]. The healthy siblings of a patient have a two-thirds probability of being carriers. When homozygosity results from maternal uniparental disomy, the father is not a carrier and the recurrence risk for siblings approaches that of the population; confirmation of the parental origin of the variants is therefore necessary before giving a recurrence risk, especially when the parents are not consanguineous [8]. In the case with a single detected allele, the risk cannot be calculated reliably until the second allele is identified [14]. An adult patient with Alazami syndrome necessarily transmits a variant to each child; the risk of having affected children depends on the carrier status of the partner, which is higher in consanguineous unions. The sources consulted do not describe offspring of patients.

8.2. Carriers and cascade testing

Carriers are clinically normal [7]. The telomere shortening described in carriers and in non-carrier offspring of carriers in the Saudi and Canadian families has no demonstrated clinical consequence and does not justify any carrier surveillance [28]. The 2023 proposal recommends offering testing to first-degree relatives, for counselling [15]. In extended consanguineous families, testing adult siblings and partners who belong to the same family allows at-risk couples to be identified; in populations with recurrent variants, such as c.1024_1030dup in Saudi families, a test targeted at the known variant is sufficient for relatives [5, 9].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the two familial variants are known and their phase confirmed, prenatal diagnosis by chorionic villus sampling or amniocentesis and PGT-M are technically possible. The use of PGT-M in Alazami syndrome is documented in a Sanger programme in Iraqi Kurdistan [47]. Prenatal ultrasound does not replace molecular testing, because IUGR is inconstant and late [7, 13].

8.4. Counselling of minors and content of the consultation

Carrier testing in healthy minor siblings has no clinical benefit in childhood and may be deferred until the age at which the individual can decide, according to the general rules for testing minors; diagnostic testing of a sibling with compatible signs is, on the contrary, indicated. The counselling consultation should address the inheritance pattern, the intrafamilial variability described (siblings with the same genotype and different manifestations), the absence of specific treatment, the manifestations that require surveillance, the possibility of a second recessive disease in consanguineous families and the reproductive options [7, 14, 30].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no population estimate of prevalence. Orphanet assigns the class "<1/1,000,000" as worldwide point prevalence, a class estimate based on the cases published at the time of annotation (10 cases or families, from the founding article), not a measurement [1]. The available figures are cumulative counts of published patients, which overlap between reviews: 17 in 2019, 23 from 11 families in 2019–2020, 24 from 12 families in 2020, fewer than 35 in 2022, 53 in 2025, fewer than 60 in 2025 and 60 in the 2026 table, to which are added the 7 patients of Sharaf-Eldin and colleagues [5, 7, 12, 14, 25, 31, 32, 34]. These counts measure publication and not occurrence: the disease is diagnosed only by exome sequencing, and underdiagnosis in regions without access to sequencing is likely [5, 34].

9.2. Geography, consanguinity and recurrent variants

Published patients come mainly from consanguineous families in the Middle East, Asia and North Africa [15]. There are descriptions from Saudi Arabia, Oman (12 patients from 8 families), the United Arab Emirates, Jordan, Iran, Turkey, Afghanistan, Algeria, Egypt, Libya, India, China and Japan [5, 9, 12, 13, 23, 29, 33, 34, 37, 42]. In Europe, there are patients from the Netherlands, Italy, Spain, France and Poland; in North America, from the US and Canada, including patients of European ancestry born to non-consanguineous parents [7, 8, 15, 25–28, 30–32, 35, 36]. Some variants recur in families of the same ethnicity — c.1024_1030dup in Saudi families, c.646+3_646+6del, c.1173T>A and c.1653_1654del in other populations of the region — which suggests a founder effect, without formal demonstration by haplotype analysis [5]. Other variants have appeared in families of distant origins, such as c.651_655del in the US and Canada and c.834dup in the US and Spain [5]. The sources consulted do not include patients from Portugal or Brazil; this absence in the sources does not demonstrate the absence of patients in these countries.

9.3. Special populations

In populations with high consanguinity, the probability of a second recessive disease in the same patient is greater, and atypical findings should lead to reanalysis of the exome [14, 30]. In boys, the hypothesis of male-predominant humoral immunodeficiency justifies particular attention to infections, still without validation in larger series [5]. In patients of non-consanguineous parents with a homozygous variant, uniparental disomy should be considered [8]. Adults are few and poorly characterised [23].

9.4. Reference networks and patient associations

In Europe, the relevant network is ERN ITHACA (European Reference Network on Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders) [17]. The Human Disease Genes website series maintains a page dedicated to LARP7, with information for professionals and families, updated in October 2026 [18]. No patient association specific to Alazami syndrome was found; for the group of primordial dwarfisms, the Oxford Desk Reference lists the Walking With Giants Foundation and, in the United Kingdom, the microcephaly support group of Contact a Family [22].

10. Illustrative Clinical Case

The case published by Fauntleroy-Love and colleagues in 2023 brings together the core phenotype and three new findings (deficient response to polysaccharide vaccine, periventricular nodular heterotopia and stroke) [15]. The patient is a boy from a Caucasian family of European origin in the US Midwest, born to non-consanguineous parents with no family history of developmental delay, delivered at 34 weeks. He spent six weeks in a neonatal intensive care unit with continuous positive airway pressure and nasogastric tube feeding, because of aspiration on the first swallowing study. The echocardiogram showed a moderate ostium secundum atrial septal defect with left-to-right shunt, and renal ultrasound showed bilateral hydronephrosis with a normal micturating cystourethrogram; newborn metabolic and hearing screening were normal. He had obstructive sleep apnoea, treated at 11 months by adenoidectomy and supraglottoplasty, more than ten episodes of otitis requiring myringotomy, multiple upper respiratory infections and self-limiting diarrhoea lasting six weeks; computed tomography showed the testes in the inguinal canals.

He was seen in the developmental paediatrics clinic at 20 months for poor weight gain, global delay and feeding difficulties. He had a developmental age of about 12 months: he sat without support, pulled to stand and cruised, waved goodbye and had no words. HC was 46 cm (−1.37 SD), weight 8.2 kg (−3.03 SD) and length 71 cm (−4.91 SD), with severe malnutrition. He had hypertelorism, telecanthus, bilateral syndactyly and overlapping of the 2nd and 3rd toes; figure 1 of the article shows the telecanthus and hypertelorism, the overlapping toes of the right foot and the brachydactyly of the 3rd toe of the left foot (https://pmc.ncbi.nlm.nih.gov/articles/PMC10388622/figure/fig1-2329048X231190784/). Oropharyngeal dysphagia with a delayed swallowing reflex led to placement of a gastrostomy [15].

At 21 months he was admitted with H. influenzae meningitis; he had received only two of the four doses of the conjugate vaccines against H. influenzae type b and pneumococcus. MRI showed periventricular white matter loss, right periventricular nodular heterotopia (figure 2, coronal T1-weighted MRI: https://pmc.ncbi.nlm.nih.gov/articles/PMC10388622/figure/fig2-2329048X231190784/), leptomeningeal enhancement, a small empyema and a 3.8 × 3 cm left anterior frontal infarct in the anterior middle cerebral artery territory (figure 3, diffusion: https://pmc.ncbi.nlm.nih.gov/articles/PMC10388622/figure/fig3-2329048X231190784/). Computed tomography angiography showed no large-vessel occlusion and revealed a retro-oesophageal right subclavian artery and a persistent left trigeminal artery. He had anaemia with haemoglobin of 6.8 g/dL, attributed to transient erythroblastopenia of childhood. The prothrombotic work-up revealed heterozygosity for factor V Leiden and lipoprotein(a) of 156 mg/dL (101 mg/dL fasting). The reassessment echocardiogram showed an atrial septal defect without haemodynamic significance and trivial mitral regurgitation, and audiometry showed sensorineural hearing loss [15].

Immunological assessment showed normal T, B and NK lymphocyte counts, normal immunoglobulins, tetanus response and CH50, and a spleen of normal size; initial pneumococcal titres were low. At 24 months he received the 23-valent polysaccharide vaccine, without an adequate response at four weeks, and started SCIg for suspected specific antibody deficiency with a history of invasive infection. The microarray showed a maternal 188 kb duplication at 8p23.1, reclassified as likely benign, and trio exome sequencing identified the variant NM_016648.4:c.728_729dup p.(Ser244GlnfsTer9) in the homozygous state, as well as heterozygosity for a pathogenic G6PC variant (carrier of glycogen storage disease type Ia). The family moved to another state and the immunological work-up had no follow-up [6, 15].

Three elements of the case deserve a critical reading. Homozygosity in parents without known consanguinity was not investigated for uniparental disomy or remote consanguinity [8]. The stroke had several concurrent factors — meningitis, factor V Leiden and elevated lipoprotein(a) — and the authors do not attribute it to the syndrome alone [15]. The decision to start SCIg rested on an inadequate response to a single vaccine, at 24 months, in a context of invasive infection; the sources consulted do not include a specific guideline for this scenario, so this course of action should not be read as routine [15]. The figures were identified from the legends in the full text of the article.

11. Prognosis and Long-term Follow-up

11.1. Prognosis

Life expectancy is not known; the oldest published patients are 42 and 44 years old, and there are no data on mortality or causes of death in the sources consulted [5, 12, 23]. Functional prognosis depends mainly on the degree of ID and on language: most patients need help with daily activities, and some adults have not acquired verbal language, whereas others have mild to moderate ID and attend adapted school programmes [5, 7, 25]. Adult height ranges from values close to normal to −10.5 SD [13, 23]. The complications with potential for severity are congenital heart disease, invasive bacterial infections in patients with antibody deficiency, stroke and infant malnutrition [12, 15]. There are no longitudinal data on treated versus untreated course, because there is no specific treatment.

11.2. Surveillance

There is no formal surveillance guideline. The table combines the 2023 proposal, the 2026 recommendations and, for growth under GH, the SGA consensus; when the sources do not define an interval, the table says so.

TSH denotes thyroid-stimulating hormone. The repeat intervals of most assessments are not defined in any published source; the concrete periodicity is a clinical decision that should be recorded in each patient's care plan.

12. Summary and Final Considerations

Alazami syndrome is an autosomal recessive disease caused by biallelic loss of function of LARP7, the chaperone of 7SK RNA that keeps the P-TEFb factor inactive and guides modification of U6 snRNA. Loss of the protein depletes 7SK, releases P-TEFb and alters splicing robustness; animal models suggest that excess P-TEFb compromises neurogenesis and that loss of Lin28 limits cell divisions in the embryo. Clinically, it is defined by the triad of growth restriction of variable severity, moderate to severe ID and a triangular facies with deep-set eyes, malar hypoplasia, broad nose, short philtrum and widely spaced teeth, with usually mild microcephaly. About one third of patients have heart disease, and the accumulated reports add oro-dental changes, genitourinary anomalies, behavioural disorders and, in boys, a possible deficiency of antibodies against polysaccharides.

About seventy patients have been published, mainly from consanguineous families in the Middle East, North Africa and Asia, but also from Europe and North America, and all were diagnosed by sequencing. Trio exome sequencing, with analysis of CNV and regions of homozygosity, is the first-line test; uniparental disomy, large deletions and intronic variants explain incomplete diagnoses and alter the recurrence risk. There is no specific treatment and there are no trials. Care rests on a baseline multisystem assessment (growth and nutrition, development, echocardiogram, immunity, kidney, hearing, spine and teeth) and on early developmental intervention. Growth hormone can only be used by extrapolation from the consensus for children born small for gestational age, and subcutaneous immunoglobulin and melatonin according to the label indications in analogous conditions; in all cases, the decision is individual. Current knowledge rests on case reports, and the priorities are a prospective natural history, validation of the immunological phenotype and clarification of the cancer risk.

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