Bleeding Disorders in Children With Genetic Diseases: A Narrative Review

ABSTRACT

Aim

The lack of data on bleeding risk assessment in children with genetic diseases is concerning given their increased care needs and risk of haemorrhagic complications compared to the general population. Identification of haemostatic disorders is crucial for implementing preventive measures and mitigating bleeding risk. This review aims to provide a comprehensive overview of genetic syndromes that predispose children to bleeding due to haemostatic dysfunction.

Methods

Genetic syndromes associated with bleeding diathesis related to haemostatic disorders were identified using the Human Phenotype Ontology. A comprehensive literature review was conducted to summarise the clinical and laboratory findings, as well as the types of haemostatic abnormalities associated with each genetic syndrome.

Results

Eighteen genetic diseases were included, with platelet dysfunction the most common cause of haemorrhagic syndrome in 17 of them. A coagulation factor deficiency has been described in four diseases. Six diseases expose patients to a risk of severe bleeding. For each genetic disorder, we detailed the mechanism of haemostasis dysfunction and the haemostasis abnormalities that may be observed.

Conclusion

Recognising haemostatic abnormalities in children with genetic diseases allows for more effective clinical management. Systematic coagulation screening is recommended for all patients with the syndromes discussed in this review.

Summary

Children with syndromic genetic diseases face an increased risk of bleeding, yet data on haemostatic assessment in this population remain scarce, necessitating a comprehensive overview. This systematic review identified 17 genetic syndromes predisposing to bleeding, most commonly due to platelet function defects and less frequently to coagulation factor disorders. Early recognition of haemostatic dysfunction in these syndromes supports preventive management, and systematic coagulation screening is recommended for affected patients.

Abbreviations

22q11DS

22q11.2 deletion syndrome

ADP

adenosine diphosphate

Ag

antigen

aPTT

activated partial thromboplastin time

ARC

arthrogryposis, renal tubular dysfunction, and cholestasis

AT

antithrombin

CDG

congenital disorders of glycosylation

EDS

Ehlers‐Danlos syndrome

GP

glycoprotein

HDCT

heritable connective tissue disorders

HPO

Human Phenotype Ontology

HPS

Hermansky‐Pudlak syndrome

LAD

leukocyte adhesion deficiencies

MGAT2

mannosyl (alpha‐1,6‐)‐glycoprotein beta‐1,2‐N‐acetylglucosaminyltransferase

NS

Noonan syndrome

PC

protein C

PF4

platelet factor 4

PFA

platelet function assay

PMM2

phosphomannomutase 2

PS

protein S

RCo

ristocetin cofactor activity

TRAP

thrombin receptor activating peptide

vWF

von Willebrand factor

WAS

Wiskott‐Aldrich syndrome

WS

Wolfram syndrome

1. Introduction

In recent decades, significant advances have been made in understanding congenital bleeding disorders, particularly the mechanisms underlying haemostatic dysfunction [1, 2, 3]. In the context of genetic diseases, haemostatic abnormalities often occur as secondary complications that may go unrecognised due to the limited volume of published data and the absence of large cohort studies. Scientific reports tend to focus on small groups or single cases, and review articles tend to address isolated syndromes rather than provide a comprehensive perspective [4, 5, 6]. A substantial proportion of affected children require invasive procedures early in life, which significantly increases the risk of perioperative bleeding [7, 8, 9]. Thus, identifying patients at high bleeding risk prior to surgical intervention is crucial for implementing effective prophylactic and therapeutic strategies [10]. This review aims to provide an overview of genetic disease in children that predispose them to bleeding diathesis due to underlying haemostatic disorders. Additionally, the review aims to help clinicians identify haemostatic abnormalities in this complex clinical setting to improve patient safety and outcomes.

2. Methods

We identified genetic diseases associated with bleeding diathesis using the Human Phenotype Ontology (HPO) database with the terms ‘abnormal bleeding’ (HP:0001892) in combination with impaired platelet aggregation (HP:0003540) and abnormality of coagulation (HP:0001928). The following conditions were excluded from the initial results: duplicates; non‐genetic diseases; constitutional bleeding disorders; bleeding syndromes not linked to a primary haemostasis defect; vascular diseases; connective tissue disorders; cases of secondary thrombocytopenia without platelet dysfunction; liver diseases; and bleeding attributed to local causes only. The sorting and classification of pathologies extracted from the HPO search was carried out by two independent reviewers, with a third reviewer intervening in the event of disagreement between the first two. Then a comprehensive search of the MEDLINE database was conducted for each eligible pathology without language restrictions. This research was conducted by two independent reviewers, then the data was pooled and validated for each pathology by a third independent reviewer. We reviewed studies, clinical data, and case reports describing bleeding symptoms, haematological findings, and underlying haemostatic pathophysiology in affected children. Primary haemostasis defects and separate coagulation factor deficiencies were analysed in isolation for each syndrome whenever possible. Studies reporting documented platelet dysfunction, abnormal laboratory findings, and clinically defined bleeding risk were given special attention.

3. Results

An initial search of HPO identified 713 diseases associated with abnormal bleeding. After removing 50 duplicates, eligibility screening was performed on 663 diseases. During this process, we excluded 51 non‐genetic diseases, 85 constitutional bleeding disorders, and 486 diseases with bleeding syndromes unrelated to haemostatic defects. Of the remaining 41 diseases, nosological groups were formed, resulting in a bibliographic review of 18 distinct diseases or disease groups (Figure 1). Primary haemostasis impairment was identified in 17 of these diseases, with platelet function abnormalities reported in 16 cases. Four distinct groups of pathologies with coagulation factor deficiencies were identified, three of which exhibited primary haemostasis disorders as well. Below we present a brief narrative review for each identified pathology. The clinical phenotypes, haemorrhagic tendencies, and underlying causes are detailed in Table 1. Tables 2 and 3 summarise the biological abnormalities related to primary haemostasis and coagulation for each genetic disease group, respectively.

FIGURE 1.

Flow chart for HPO search. CDG, congenital disorder of glycosylation; HPO, Human Phenotype Ontology.

TABLE 1.

Summary of the clinical phenotype, bleeding phenotype, and mechanism of haemostasis impairment for each syndrome.

Syndrome	Clinical phenotype	Bleeding phenotype	Mechanism of haemostasis dysfunction
22q11.2 deletion syndrome	Facial dysmorphism, velopharyngeal insufficiency, cardiac defects, immune deficiency, hypocalcemia, autoimmune problems, learning difficulties, psychiatric disorders	Mild to moderate	Macrothrombocytopenia, GPIb defect
Leukocyte adhesion deficiency III	Immune deficiency	Severe	GPIIb‐IIIa dysfunction
Filamin A related disease	Cerebral malformations, cardiovascular abnormalities, Ehlers Danlos syndrome‐like phenotype, chronic respiratory troubles	Mild	Thrombopenia, cytoskeletal defect
MYH9‐related disease	Hearing loss, presenile cataract, renal disease	Severe	GPIIb/IIIa dysfunction, macrothrombocytopenia, cytoskeletal defect
DIAPH1‐related disease	Hearing loss	Mild	Macrothrombocytopenia; cytoskeletal defect
Wiskott‐Aldrich syndrome	Eczema, immune deficiency, autoimmunity, malignancy	Severe	Microthrombocytopenia, cytoskeletal defect
Lowe syndrome	Neonatal hypotonia, cognitive delay, congenital cataract, renal Fanconi tubulopathy	Mild to moderate	Thrombopenia, cytoskeletal defect, lyzosomal dysfunction
Arthrogryposis renal dysfunction cholestasis syndrome	Arthrogryposis, renal tubular dysfunction, cholestasis	Mild to moderate	α‐granules deficiency
Hermansky‐Pudlak syndrome	Oculocutaneous albinism, pulmonary fibrosis, granulomatous colitis, immune defects	Severe	δ and α granule deficiency
Chediak‐Higashi syndrome	Hypopigmentation of skin, hair, and eyes, recurrent bacterial infections, neurologic symptoms	Moderate to severe	δ granule deficiency
Jacobsen Syndrom	Facial dysmorphism, developmental delays, congenital heart defects, Paris‐Trousseau thrombopenia, skeletal abnormality, caratacts, immunodeficiency, kidney malformation	Mild	δ and α granule deficiency
Glycogen storage disease 1a	Hypoglycaemia, hepatomegaly, growth retardation, secondary metabolic abnormalities	Mild	Metabolic energy defect, Willebrand factor deficiency
Sitosterolemia	Xanthomas, arthritis, arthralgia, short stature, accelerated atherosclerosis, premature cardiac death	Mild to moderate	Macrothrombocytopenia, GPIb and GPIIa defect
Stormorken syndrome	Muscle fatigue, asplenia, miosis, anaemia, migraine, dyslexia, ichthyosis, short stature	Variable bleeding	Thrombocytopenia, calcium regulation
Noonan syndrome	Short stature, dysmorphic facial features, webbed neck, congenital heart defects, hypoplastic external genitalia and cryptorchidism, sternal deformity, developmental delay, lymphatic hypoplasia	Mild to moderate	Platelet dysfunction, mild willebrand factor and coagulation factors deficiency
Gaucher disease	Hepatosplenomegaly, liver and bone pain (painful bone crises, avascular necrosis)	Moderate	Thrombopenia, platelet dysfunction, coagulation factors deficiency
CDG syndrome	Hypotonia, cerebellar ataxia, mental retardation, facial dysmorphia, cytolysis and hepatic fibrosis, chronic diarrhoea, cardiomyopathy, nephrotic syndrome, hypogonadism	Moderate to severe	GPIb deficiency (MGAT2), Willebrand factor deficiency (PMM2), coagulation factors and regulators deficiency
Monosomy 13q14	Growth retardation, facial dysmorphisms, moderate to severe mental retardation, brain malformation, cardiovascular, musculoskeletal and urogenital developmental abnormalities	Mild	Factor VII and X deficiency

Abbreviations: CDG, congenital disorder of glycosylation; GP, glycoprotein; MGAT2, mannosyl (alpha‐1,6‐)‐glycoprotein beta‐1,2‐N‐acetylglucosaminyltransferase; PMM2, phosphomannomutase 2.

TABLE 2.

Details of primary haemostasis abnormalities that may be found in each syndrome.

	Platelets count	Mean platelet volume	Platelets morphology	Platelet function assay (PFA‐100)	Platelet function test	Platelets glycoprotein	Granules study	Electronic microscopy	von Willebrand factor
22q11.2 deletion syndrome	↓ (mild)	↑ (mild)	—	ADP: ↑ Epinephrin: ↑	↓ With TRAP, ristocetin, ADP	↓ GPIb/GPIIb ratio	—	—	—
Leukocyte adhesion deficiency III	—	—	—	ADP: ↑ Epinephrin: ↑	↓ With various agonists Normal with ristocetin	—	—	—	—
Filamin A related disease	↓	↑	Anisocytosis with both giant and normal platelets	—	↓ Collagen	—	—	—	—
MYH9‐related disease	↓	↑	Giant platelets	—	↓ With epinephrin, wave with ADP	—	—	—	—
DIAPH1‐related disease	↓	↑	Giant platelets	—	↓ With ADP and collagen	—	↓ In α‐granules and δ‐granules release	—	—
Wiskott‐Aldrich syndrome	↓	↓	Micro platelets	ADP: ↑ Epinephrin: ↑	↓ With epinephrin, ADP, collagen	—	—	Abnormal ultrastructure and reduction in granule content	—
Lowe syndrome	↓	—	—	ADP: ↑ Epinephrin: ↑	—	—	—	—	—
Arthrogryposis‐renal dysfunction‐cholestasis syndrome	—	↑	Large and pale agranular platelets	Epinephrin: ↑	↓	—	↓ PF4, vWF, β‐TG, TSP‐1, fibrinogen	↓ α‐granules ↑ δ‐granules	—
Hermansky‐Pudlak syndrome	—	—	—	—	Severely reduced or absent second wave	—	↓ Serotonin and ADP ↑ ATP/ADP ratio	ø δ‐granules	—
Chediak‐Higashi syndrome	—	—	—	ADP: ↑ Epinephrin: ↑	↓ With various agonist ↓ Absent secondary wave with epinephrin	—	↑ ATP/ADP ratio ↓ Serotonin, calcium, ADP, uptake of serotonin After simulation: ↓ of serotonin, ATP and ADP release	↓ δ‐granules giant inclusion bodies	—
Jacobsen syndrome	↓	↑	Large platelets	ADP: ↑ Epinephrin: ↑	↓ With epinephrin, and collagen	—	—	Fused α‐granules ↓ δ‐granules	—
Glycogen storage disease 1a	—	—	—	ADP: ↑ Epinephrin: ↑	↓ With all agonist	—	—	—	↓ vWF: Ag ↓ vWF: Rco
Sitosterolemia	↓	↑	Large platelet surrounded by a circle of vacuoles	ADP: ↑ Epinephrin: ↑	↓ With ristocetin varaible responses to other agonists	GPIIb: ↓ GPIbα: ↓	—	—	—
Stormoken syndrome	↓	—	—	—	↓ With ADP, collagen	—	After stimulation: ↓ of ATP release	—	—
Noonan syndrome	↓	—	—	ADP: ↑ Epinephrin: ↑	↓ With collagen, ADP, epinephrine, arachidonic acid, ristocetin.	—	—	—	↓ vWF: Ag ↓ vWF: RCo
Gaucher Disease	↓	—	—	ADP: ↑ Epinephrin: ↑	↓ With various agonists	—	—	—	↓ vWF: Ag ↓ vWF: Rco
CDG syndrome	—	—	—	—	—	—	—	—	↓ vWF: Ag ↓ vWF: Rco (PMM2 only)

Abbreviations: ADP, adenosine diphosphate; Ag, antigen; GP, glycoprotein; PFA, platelet function assay; PMM2, phosphomannomutase 2; RCo, ristocetin cofactor activity; TRAP, thrombin receptor activating peptide; VWF, von Willebrand factor.

TABLE 3.

Details of coagulation abnormality that may be found in each syndrome.

	PT (s)	aPTT (s)	Coagulation factor	Anticoagulant factor
Monosomy 13q34	↑	↑	↓ FVII, FX
Noonan syndrom	↑	↑	↓ FVIII, FIX, FXI FXII, FXIII
Gaucher disease	↑	↑	↓ All cloting factor exept FXIII and fibrinogen
CDG syndrom	↑	↑	↓ FII, FVII, FVIII, FIX, FX, FXI	↓ AT, PC, PS

Abbreviations: aPTT, activated partial thromboplastin time; AT, antithrombin; CDG, congenital disorder of glycosylation; PC, protein C; PS, protein S.

3.1. Primary Haemostasis Impairment (Tables 1 and 2)

3.1.1. Platelet Receptor Defects

This section focuses on defects involving platelet receptors. 22q11.2 deletion syndrome (22q11DS) is the most prevalent microdeletion syndrome. It is characterised by platelet abnormalities, particularly macrothrombocytopenia caused by haploinsufficiency of the GPIBB gene, which encodes a component of the GPIb‐IX‐V complex essential for platelet adhesion and aggregation [11]. Patients with 22q11.2 deletion often have lower platelet counts, increased platelet volume, and impaired platelet function, which may lead to an increased risk of bleeding [12]. The severity of platelet dysfunction varies among individuals and is influenced by the specific deletion size and gene expression, but these haematological features are consistent markers of the syndrome [13].

Leukocyte adhesion deficiency type III (LAD‐III) is a rare autosomal recessive disorder caused by mutations in the FERMT3 gene encoding Kindlin‐3, a key protein for β‐integrin activation. Kindlin‐3 is essential for platelet integrin αIIbβ3 activation, and its deficiency leads to severely impaired platelet aggregation with normal platelet counts but a bleeding phenotype similar to Glanzmann thrombasthenia [14]. Patients with LAD‐III experience severe mucocutaneous bleeding from early infancy, and their platelet function abnormalities improve after haematopoietic stem cell transplantation [15]. Despite normal expression of GPIIb/IIIa on platelets, its activation is defective, resulting in markedly prolonged closure times and severely impaired aggregation with all agonists [16].

3.1.2. Platelet Cytoskeleton Defects

Another important cause of thrombopathy is impairment of the platelet cytoskeleton. Filamin A is a crucial protein for linking the actin cytoskeleton to adhesive receptors in platelets, maintaining their structural integrity and proper function [17]. Deficiency in filamin A causes abnormal platelet morphology (giant and anisocytotic platelets), thrombocytopenia, and impaired platelet aggregation, especially in response to collagen, leading to unstable clot formation and bleeding tendencies [18]. Patients with filamin A defects often experience mucocutaneous bleeding or menometrorrhagia due to these platelet function abnormalities [19].

MYH9‐related disorders are autosomal dominant syndromes characterised by macrothrombocytopenia and sometimes hearing loss, early cataracts, and kidney disease. The MYH9 gene encodes non‐muscle myosin heavy chain IIA, and defects impair cytoskeletal reorganisation, which leads to platelet dysfunction and abnormal large platelets [20]. Bleeding symptoms are usually mild, correlating with platelet count, but platelet functional defects such as impaired contractility and clot retraction also contribute to bleeding risk [21]. Some patients may experience severe bleeding like menorrhagia, and recent studies show that antifibrinolytic treatment can improve haemostasis in these disorder [22].

DIAPH1‐related thrombocytopenia is characterised by moderate macrothrombocytopenia associated with a low or mild bleeding risk [23]. Patients typically have enlarged platelets and a moderately reduced platelet count, but spontaneous bleeding is uncommon or mild, often limited to minor mucocutaneous bleeding like nosebleeds or gum bleeding. Although platelet function may be variably impaired, the overall bleeding tendency is considered mild, with significant bleeding episodes usually occurring only in the context of surgery, trauma, or other haemostatic challenges [24]. Thus, while careful monitoring is advised, most individuals with DIAPH1‐related thrombocytopenia live with minimal bleeding complications despite their low platelet counts [25].

Wiskott‐Aldrich syndrome (WAS) is an X‐linked disorder characterised by microthrombocytopenia, with small, dysfunctional platelets, leading to bleeding symptoms that can range from skin petechiae to severe intracranial haemorrhages [26]. The syndrome involves abnormalities in the WAS protein, essential for actin polymerisation, which results in defective platelet production and increased destruction, often causing life‐threatening bleeding events [27]. Platelets in WAS also exhibit ultrastructural abnormalities, including reduced granules and poor aggregation response to stimuli like epinephrine, ADP, and collagen [28].

Lowe syndrome, caused by defects in the OCRL1 gene, results in abnormal actomyosin cytoskeleton reorganisation affecting megakaryocyte maturation and platelet production [6]. Patients show mild thrombocytopenia and platelet dysfunction characterised by prolonged closure times, despite normal aggregation, granule release, and receptor expression [29]. Bleeding mainly occurs during invasive procedures, making thorough preoperative haemostatic assessment crucial [30].

3.1.3. Defects in Granule Formation

We will now focus on the pathologies responsible for platelet granule defects. ARC syndrome is an autosomal recessive multisystem disorder characterised by a bleeding tendency due to α‐granule deficiency in platelets, which appear large and pale on blood smears [31]. Although platelet counts are usually normal, electron microscopy shows an absence of α‐granules and their contents, leading to variably impaired platelet aggregation. Patients may experience both spontaneous and post‐procedural bleeding complications [32].

Hermansky‐Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterised by oculocutaneous albinism, a bleeding tendency due to platelet dysfunction, and sometimes additional complications such as pulmonary fibrosis and granulomatous colitis [33]. The bleeding is caused by defective formation and function of lysosome‐related organelles, particularly dense granules in platelets, leading to impaired clotting and easy bruising, nosebleeds, and bleeding after procedures or trauma [2].

Chediak‐Higashi syndrome is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, severe immunodeficiency with recurrent infections, bleeding tendency, and progressive neurological dysfunction resulting from mutations affecting lysosomal trafficking [34]. Platelet abnormalities include reduced dense granules and hyposecretion of ATP, ADP, calcium, and serotonin, which impair the secondary wave of platelet aggregation leading to bleeding symptoms ranging from minor bruising to petechiae [35]. However, significant haemorrhaging is not consistently observed during some surgical procedures, highlighting variable bleeding risk in affected patients [36].

Jacobsen syndrome is caused by a terminal deletion on chromosome 11q22, including the FLI1 gene essential for megakaryocyte differentiation and platelet formation [37]. This leads to Paris‐Trousseau syndrome, characterised by neonatal thrombocytopenia that often improves, but persistent platelet dysfunction due to abnormal large fused alpha granules and reduced dense granules causes impaired clotting factor release and bleeding tendency [38]. Bone marrow shows dysmegakaryopoiesis with immature megakaryocytes, and platelets demonstrate diminished aggregation to low‐dose epinephrine and collagen, resulting in a mild but lifelong increased bleeding risk [39].

3.1.4. Platelet Dysfunction in Metabolic Disorders

Finally, certain diseases alter platelet function through metabolic abnormalities or overload. Glycogen storage disease type I is associated with bleeding in up to 20% of patients, presenting as easy bruising, epistaxis, and bleeding around procedures [40]. The bleeding diathesis is mainly due to acquired platelet dysfunction, including abnormal platelet aggregation, prolonged closure times, reduced adhesion, and decreased prothrombin consumption. Mild von Willebrand factor deficiency may also contribute to this bleeding risk [41].

Sitosterolemia is an autosomal recessive disorder characterised by accumulation of plant sterols, leading to hemolytic anaemia, macrothrombocytopenia, bleeding, and splenomegaly [42]. Bleeding symptoms range from mild to requiring platelet transfusions postoperatively. Platelet dysfunction is caused by incorporation of plant sterols into the platelet membrane, resulting in hyperactivation, reduced expression of GPIIb and GPIbα, and disruption of the GPIbα‐FlnA linkage, impairing platelet adhesion and aggregation [43].

Stormorken syndrome is an autosomal dominant disorder caused by mutations in the STIM1 gene, leading to thrombocytopenia and defective calcium homeostasis that impairs platelet signalling [44]. Patients typically present with mucocutaneous bleeding, haematuria, and skin purpura, alongside muscle weakness, miosis, and other multisystemic features [45]. Laboratory findings include reduced platelet counts, diminished aggregation responses to ADP and collagen, and decreased ATP secretion, reflecting platelet dysfunction [46].

3.2. Coagulation Impairment (Tables 1 and 3)

3.2.1. Isolated Clotting Factor Deficiencies

A partial deletion of the 13q34 region causes combined deficiency of coagulation factors VII and X due to loss of the F7 and F10 genes [47]. This condition leads to prolonged prothrombin time with normal activated partial thromboplastin time (aPTT) and reduced levels of these factors. Bleeding symptoms are usually mild or absent, but surgical procedures may require factor replacement or antifibrinolytic therapy for management [48].

3.2.2. Combined Clotting Factor and Platelet Defects

In certain pathologies, coagulation factor deficiency appears to be the primary factor; however, platelet dysfunction is also considered an additional risk factor for bleeding.

Haemostatic abnormalities in Noonan syndrome (NS) are common and vary widely, with bleeding ranging from mild to severe, particularly after surgery [49]. Laboratory findings often include modestly prolonged aPTT and deficiencies in coagulation factors XI, VIII, and XII, frequently accompanied by platelet function defects [50]. There is a strong association between abnormal ADP‐induced platelet aggregation and clinically significant bleeding, so thorough bleeding risk assessment is essential before invasive procedures in NS patients [51].

In Gaucher disease type I, bleeding occurs in about 30% of patients, mainly due to thrombocytopenia caused by hypersplenism and bone marrow infiltration [52]. Significant haemorrhage can also happen despite normal platelet counts, suggesting additional haemostatic defects such as coagulation factor deficiencies (notably factors V and X), prolonged PT/aPTT, and platelet function abnormalities. Bleeding is typically mild and mucocutaneous, but peripartum and postoperative haemorrhages have been reported, highlighting the need for careful haemostatic evaluation, especially perioperatively [53].

Congenital disorders of glycosylation (CDG) are multisystem diseases caused by defective glycoprotein and glycolipid synthesis, often leading to coagulation abnormalities [54]. The most common form, PMM2‐CDG, is associated with deficiencies in antithrombin, factor XI, and occasionally proteins C and S and factors IX, II, V, VII, and X, resulting in varied bleeding and thrombotic manifestations [55]. Some CDG subtypes, like MGAT2‐CDG, show increased bleeding risk possibly due to GP Ib deficiency, and neonatal bleeding has been reported in others, highlighting the importance of preventive management and close haemostatic monitoring [56, 57].

4. Discussion

This review describes haemostatic impairment associated with 17 genetic syndromes. Most of these syndromes involve abnormal platelet function, while the rest are characterised by defects in coagulation. The clinical presentation of bleeding diathesis in children with congenital syndromes is highly variable and is often underrecognized, particularly in the absence of haemostatic challenges, such as surgery or injury. The majority of these abnormalities affect platelet function and often do not show up in blood counts, so it is important that physicians treating patients are well informed [3]. Specific platelet function tests in laboratories specialising in platelet function are necessary in many cases [35, 58]. Syndromes such as Hermansky‐Pudlak syndrome typically cause mild spontaneous mucocutaneous bleeding but can lead to severe haemorrhaging following procedures or trauma [33]. Importantly, the bleeding phenotype is not consistent even within the same syndrome. For instance, in 22q11.2 deletion syndrome, heterozygous loss of platelet glycoprotein GPIb‐V‐IX variably affects platelet function, which makes clinical prediction difficult [13]. Many of these children face an increased risk of invasive procedures; for instance, surgery is often necessary for cardiac or urogenital abnormalities in patients with Noonan syndrome [4]. Therefore, early identification of an underlying haemostatic disorder is critical to preventing perioperative and spontaneous bleeding. Previous studies have generally focused on a single genetic disease or a few genetic diseases; in contrast, this review provides a broader spectrum of genetic syndromes associated with clinically meaningful haemostatic impairment. However, this methodology may not capture all genetic syndromes associated with bleeding due to a haemostasis disorder, particularly rare conditions for which evidence is limited to case reports and series. For some conditions, a bleeding syndrome related to haemostasis is suspected, but there is no formal proof or adequate laboratory testing. One clear example is the group of heritable connective tissue disorders (HDCT), such as Ehlers‐Danlos syndrome (EDS), in which patients exhibit vascular fragility and bleeding; however, laboratory platelet function and coagulation tests often appear normal [59]. These disorders present unique diagnostic challenges because routine in vitro tests fail to account for vessel wall interactions and other extrinsic factors. Laboratory investigation of platelet aggregation and clotting factors in patients with EDS or other HDCT usually yields normal results; therefore, connective tissue disorders present physicians with the challenge of diagnosing a bleeding diathesis related to primary haemostasis impairment that current methods cannot detect [60]. In vitro platelet function testing by light transmittance aggregometry represents an incomplete in vivo scenario. Specifically, the model lacks vessel wall components. Further research is needed to better understand the origin of these vascular defects and their impact on platelet‐vessel wall interactions. Developing and using novel assays to evaluate haemostasis may further improve risk stratification and care for this vulnerable population.

5. Conclusion

This review highlights 18 congenital syndromes that can lead to significant bleeding in paediatric patients due to clinically meaningful haemostatic abnormalities. Recognising haemostatic defects early in children with genetic disease is essential for preventing severe bleeding and optimising clinical outcomes. Most of these disorders primarily involve platelet dysfunction, which often evades detection by standard coagulation assays. This underscores the necessity of specialised evaluation. However, clinical and laboratory abnormalities are not always predictive of bleeding risk; some patients experience bleeding events despite normal routine test results. Therefore, the systematic involvement of a haemostasis specialist is recommended for all children with one of the discussed syndromes, especially before invasive procedures.

Author Contributions

Raphaelle Cagol: data curation, investigation, resource, writing – original draft. Mariam Sbeity Barakat: data curation, investigation, resource, writing – original draft. Marjolaine Willems: visualization, validation, writing – review and editing. Tasnime Akbaraly: visualization, validation, writing – review and editing. Biron‐Andreani Christine: visualization, validation, writing – review and editing. Isabelle Diaz: visualization, validation, writing – review and editing, supervision. Alexandre Theron: conceptualization, writing – original draft, methodology, data curation, project administration, visualization, validation, supervision.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Access to raw data is available on request from the authors.