Macrocephaly and Finger Changes: A Narrative Review

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.


Introduction
Congenital anomalies are common, occurring in at least 2-3% of infants and are major drivers of mortality and morbidity [1].Understanding the etiology of malformations may aid the search for modifiable causes of abnormalities [1].Recent progress in molecular sciences has revealed, aside from monogenic disorders, a large array of non-Mendelian genetic contributors to this pathology [1].However, clinical observation is invaluable in guiding the examinations, and the distance from the bench to the bedside is shortened by the astute clinicians who notice subtle disease features.
We aimed to review what follows the diseases which are associated with macrocephaly and finger changes, in the hope of helping the practitioners facing these anomalies that either manifest in infancy or later during development.The manuscript combines elements of both narrative and synthetic reviews, providing an overview of the subject matter by synthesizing information from various sources.The list of rare disorders characterized by the association of "macrocephaly with finger changes" was generated using FindZebra database and subsequently cross-referenced with data from the OMIM database.Furthermore, a search was conducted using PubMed with the following medical subject headings (MeSH terms): (macrocephaly OR megalencephaly OR hydrocephalus) and (finger OR digits OR hands OR upper extremity OR nails).The English language filter was the single one applied in the search.However, single mentions of a feature of interest that were not included in OMIM were excluded.
Macrocephaly (MC) is caused by an increase in the head size, defined as an increased occipitofrontal circumference of above two standard deviations or greater than the 97th percentile corresponding to the age, sex, and gestational age.
According to Barbier et al. (2013), the mean normal head circumferences by gestational age from 24 to 40 weeks are as follows (in cm): at 24 weeks, it is 22.7 for boys and 22.1 for girls.At 26 weeks, it increases to 24.6 for boys and 23.8 for girls.By 28 weeks, the mean head circumference reaches 26.3 for boys and 25.7 for girls.Advancing to 30 weeks, it measures 28.3 for boys and 27.7 for girls.At 32 weeks, the average head circumference is 30.1 for boys and 29.6 for girls.Continuing to 34 weeks, it grows to 31.9 for boys and 31.5 for girls.By 36 weeks, it reaches 33.5 for boys and 33.1 for girls.At 38 weeks, it is 34.6 for boys and 34.0 for girls.Finally, at 40 weeks, the mean head circumference is 35.2 for boys and 34.6 for girls [2].References of normal mean head circumference on gestational age (24-40 weeks) are listed in the Supplementary Materials Table S1.When the occipitofrontal circumference exceeds three standard deviations, neurogenetic disorders are usually associated [3][4][5][6].Single-gene disorders are responsible for some MC cases, but most MC cases have uncertain etiology [7].
Megalencephaly (ME) is defined as the enlargement of the brain parenchyma of more than two standard deviations above the age-related mean.ME is caused by the abnormal size or number of dysfunctional neurons and/or glia.Brain development is controlled by multiple signaling pathways involved in proliferation, migration, and organization of neurons and glia (mTOR, Ras/MAPK, and SHH pathways) [4,8,9].Copy number variations (CNVs), which are an important source of genetic variability, can also be considered causative factors of ME, together with mosaicism and epigenetic mutations [8,9].Usually, ME is associated with developmental disabilities and is often more syndromic than MC [10].Autism is often associated with ME or MC.The defective neuronal migration resulting in abnormal laminar positioning of cortical projection neurons, along with the inappropriate synaptic pruning and arborization, and with the consequently increased dendrite number and size all possibly connect MC with autism [3].
HC is a common condition caused by physical or functional obstruction of the cerebrospinal fluid (CSF) flow, leading to active distention of the ventricular system [11][12][13].CSF is produced by the choroid plexi, passes through the ventricular system to the subarachnoid space, and it is absorbed into the venous sinuses and undergoes systemic circulation.HC has both genetic and environmental causes and can be congenital or acquired.When acquired, HC is considered a complication of various conditions such as hemorrhage, infection, neoplasia, or medication taken during pregnancy acting upon a structurally normal brain.Patients with HC can present other physical abnormalities or can have predominantly brain anomalies [11].L1CAM mutations are the main genetic causes of isolated HC [3,5,11].
MC can be present at birth or can occur later during postnatal growth.MC, affecting up to 5% of children, is often benign familial or due to benign external HC and may be associated with over 200 genetic disorders or other progressive etiologies [3].
MC is attributed to the increase in size of any of the cranium components (brain, cerebrospinal fluid, blood, or bone) or to increased intracranial pressure, The hypertrophic or hyperplastic structure involved may give a clue on the underlying pathology.The general causes of MC with examples are listed in Supplementary Materials Table S2.
Excessive CSF may increase the size of the cephalic extremity, causing HC, either obstructive (such as in brain tumors, Chiari malformation, Dandy-Walker syndrome malformation, aqueductal stenosis) or communicative, due to deficient CSF resorption or altered blood circulation within the brain.The benign enlargement of the subarachnoid space or cerebral hemorrhages may produce similar effects.Increased intracranial pressure (in infections, metabolic disorders, pseudotumor cerebri, intoxications etc.) may result in MC [3,5,11,[14][15][16].
Bone disorders involving the bone marrow (as in thalassemia) or the bone structure (in rickets), skeletal dysplasia (achondroplasia, cleidocranial dysostosis, osteogenesis imperfecta, hyperphosphatasia, osteopetrosis, osteopathia striata with cranial sclerosis and others) may be associated with MC.
The genetic mechanisms underlying the development of head bones and of extremities are complex.Excessive growth may be caused by alteration of the complex interaction between the genetic, epigenetic, and hormonal factors orchestrating human growth [17].
The etiopathogenesis of many overgrowth syndromes has been recently clarified.The overgrowth may be generalized or segmental, interesting one or a few regions of the body.The latter is often due to overactivating mutations of PI3K/AKT/mTOR.Sometimes the mutations appear in a mosaic manner, and the genetic diagnosis is not straightforward.A head circumference of ≥98%, even in the absence of other findings, may be associated with autism or intellectual disability [17].The PI3K/AKT/mTOR pathway is closely related to the RAS/MAPK pathway [18].In some overgrowth syndromes, variants in epigenetic regulators are associated with disease occurrence, such as variants of histone methyltransferases NSD1 in Sotos syndrome and EZH2 in Weaver syndrome [19,20].Other extracellular modulators may result in certain skeletal dysplasias with skull and extremities involvement [21].
Some of the MC cases are related to the premature fusion of one or more cranial sutures of the skull called craniosynostosis [22].Cranial sutures, fibrocellular structures separating the skull bones plates, enable the skull growth in coordination with the developing brain [22].The premature fusion of a suture may allow the compensatory growth of other parts to accommodate the enlarging brain, resulting in specific deformities [22].Not all craniosynostoses evolve with MC, some of them do not change in the head size or shape, while the others might result in brachycephaly, or other vault morphology defects [23].In the genetics of craniosynostoses, the fibroblast growth factor receptors (FGFR) play an important role [24].Genes associated with skeletal diseases and ME, such as FGFR-associated craniosynostosis syndromes, RAS pathway-associated syndromes and PI3K-AKT pathway associated ME syndromes have also been involved in HC pathogenesis.Growth factors (like epidermal, vascular, insulin-like EGF, VEGF, IGF3, etc.) influence the pathways in some overgrowth syndromes as well [19].
During development, the skull bones grow in a spatially and temporally coordinated fashion [25].Premature fusion of one or multiple cranial sutures may lead to craniosynostosis, leading to head size or morphology alterations [23].About 15% of the craniosynostosis cases are syndromic [23].Calvaria bones have a dual embryonic origin, namely from the cranial neural crest cells and from paraxial mesoderm and ossified directly through intramembranous ossification [25].The frontal and parietal calvaria bone origin from the supraorbital arch mesenchyme, which acts as an "organizer" for the upper skull bones [25].Angiogenesis is necessary for intramembranous ossification and for enchondral bone formation [23].
The signaling pathways for the calvarial bones include the Wnt signaling pathway and its effectors such as TWIST1, and transcription factors such as the forkhead-domaincontaining Fox family and Twist1 (basic-helix loop-helix transcription factor), along with transcription factors such as Msh Homeobox1 (Msx1), and 2 (Msx2), Runt Related Transcription factor 2 (Runx2), and Osterix (Osx/Sp7).Other factors involved in the frontal and parietal bone development are the Transforming Growth Factor Receptor beta II (TGF beta RIi) or Sp8 (Specificity Protein 8, the FGF8 regulator) [25].
For the sutures, major cellular signaling pathways (WNTs, BMPs, FGFs and others) produce a complex set of instructions for the undifferentiated mesenchymal cells to become osteoblasts lineage cells and then to progress to osteocytes [23].
Premature suture closure may result from disruption in the multistep and finely tuned process involving the development, influenced by genetic, environmental, and other intervening factors [23].The core set of transcription factors and signaling pathways involved in the skull bone development may also be disrupted into the acral appendicular skeleton development.
In the extremities, proliferating chondrocytes in the epiphyseal plate of long bones underlie the skeletal growth [17].Chondrocyte proliferation in the growth plate is increased by the Indian Hedgehog (IHH), which stimulates PTH-related protein (the IHH-PTHrP pathway) and bone morphogenetic protein (BMP) and is decreased by the FGF-FGF3 pathway [17].Chondrocyte hypertrophy is inhibited by the IHH-PTHrP pathway and stimulated by thyroid hormones through the Wnt4 (Wingless-int4)-beta-catenin pathway [17].Both chondrocyte proliferation and hypertrophy are stimulated by the growth hormone (GH) insulin-like growth factor 1 (IGf1) pathway [17].

Causes of Macrocephaly and Finger Changes
In the presence of MC, any other morphological changes, even subtle and discreet, may provide clinical clues for the clinician to identify a certain pathology.The differential diagnosis of finger changes in the context of MC is vast.
The many acral changes possibly involving the hands can constitute valuable hints for the examiner.Polydactyly may be found along with enlarged head in several syndromes (Table 1).Camptodactyly refers to flexural deviation in the proximal interphalangeal joint, while clinodactyly to the deviation in the radioulnar plan distal to the metacarpophalangeal joint [26].Finger tapering is defined as the gradual reduction in girth of the digit from proximal to distal [27].Many of the conditions evolving with the cranial and acral changes are complex syndromes with pluriorganic involvement, including cerebral, with developmental, neurologic, and psychiatric features (detailed elsewhere).

Skeletal Dysplasias
Skeletal dysplasias are important causes of familial MC [8].Achondroplasia evolves with ME, and it gives rise to specific facial features including frontal bossing and midface hypoplasia, thoracic kyphosis, lumbar lordosis, short stature, brachydactyly, and "trident hand deformity" [98].In the nail-patella syndrome, a high forehead with receding hairline, a lean trunk, and hypoplastic or absent nails are also noted [98].Pycnodysostosis, from the osteopetrosis disease spectrum, probably the disease of Toulouse-Lautrec, may evolve with MC and manifest in frontal bossing, short stature, and the acro-osteolysis of the terminal phalanges [69].

Inherited Metabolic Disorders
Inherited metabolic disorders comprise various conditions, each with unique clinical presentations.Several of these conditions, including Mucopolysaccharidoses, Gangliosidosis, Alpha-mannosidosis type I, and Peroxisome Biogenesis Disorders, are characterized by MC and finger changes [16].Mucopolysaccharidoses (MPS) represent a group of lysosomal storage disorders (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs) due to deficiencies in specific enzymes involved in their degradation.Alongside skeletal abnormalities and developmental delay, individuals with MPS may present MC, attributed to the accumulation of GAGs in the brain and subsequent HC.Gangliosidosis type I, a subtype of GM1 gangliosidosis, is caused by a deficiency in the enzyme named β-galactosidase, leading to the accumulation of GM1 ganglioside primarily in the central nervous system.MC is a common finding in affected individuals, often accompanied by typical facial features and skeletal abnormalities.Finger changes, such as claw hand deformities, can also occur due to progressive skeletal dysplasia.Alpha-mannosidosis type I is a rare autosomal recessive disorder resulting from a deficiency in the enzyme, alpha-mannosidase.MC may manifest in affected individuals, likely due to cerebral edema and HC.Additionally, skeletal abnormalities such as dysostosis multiplex can lead to distinctive changes in the fingers, including the shortening and thickening of the digits.
Peroxisome Biogenesis Disorders (PBD) are a group of autosomal recessive diseases characterized by impaired peroxisome assembly and function.Some forms of PBD may present with MC, likely due to associated brain anomalies.Finger changes may also occur, with variability depending on the specific subtype of PBD and its clinical features [16,84].

Overgrowth Syndromes
The overgrowth syndromes are a heterogenous group of rare disorders characterized by excessive growth, either generalized or segmental, associated with MC and often other additional features [120].The general term of PROS (PIK3CA-Related Overgrowth Spectrum) was agreed upon to cover all known and emerging clinical diseases associated with somatic mutations in PIK3CA.For example, within this spectrum, various entities have been described with different degrees of overgrowth associated with vascular anomalies (see Figure 1).Overlap syndromes are best understood as the clinical picture of a spectrum of diseases rather than the result of an enumeration of clinical criteria.Despite being caused by the same mutations in PIK3CA, the clinical course and outcomes of neonates with CLAPO syndrome (OMIM 613089-associating capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth) and MCAP (megalencephaly-capillary malformation) syndrome are different [121].In CLAPO syndrome, overgrowth is not always obvious, MC is absent, and involvement tends to be segmental rather than generalized.Facial asymmetry often stems from vascular factors.It is crucial to differentiate apparent asymmetry from genuine overgrowth due to hyperplasia or hypertrophy, as seen in CLAPO and PROS syndromes [122].syndrome.Dysregulated PI3K-AKT signaling, involving PDK1 (phosphoinositide-dependent kinase, RTKs (receptor tyrosine kinases), and PI3K activation, leads to abnormal cell growth and proliferation.Dysregulation manifests in various disorders such as PROS (PIK3CA-related overgrowth spectrum), HMEG (hemimegaloencephaly), MCAP, and MPPH (megalencephaly-polymicrogyria-polydactylyhydrocephalus) syndrome.Mutations in TSC1 and TSC2 (tuberous sclerosis complex 1 and 2) further contribute to overgrowth disorders, highlighting genetic complexity.
HC may belong to various dysmorphic syndromes including RASopathies, disorders caused by germline mutations of the RAS/MAPK signaling pathway, or its regulators [3,105,107,125].Glomus tumors of the fingers (benign neoplasms that arise from the glomus body, a specialized thermoregulatory shunt which is concentrated in the fingers and toes) are associated with neurofibromatosis and their appearance is determined by the loss of neurofibromin function [126,127].In neurofibromatosis type 1 (NF1), a common AD syndrome with variable expressivity, MC may be due to ME and is frequently associated to a short stature [9].Fingers in NF1 may be affected by neurofibromas, glomus tumors, bone enlargement, pseudarthrosis of the forearm or hand bones, etc. [128].Legius syndrome has similar cutaneous changes as NF1 and may have MC, but other non-pigmentary disease features of NF1 are lacking [129].
Nevoid Basal Cell Carcinoma Syndrome (Gorlin-Golitz syndrome or Gorlin syndrome) is marked by various signs of abnormal development, including macrocephaly, mild hydrocephalus, intracranial calcification, and EEG abnormalities.Anomalies in the ribs and vertebrae, brachydactyly, short fourth metacarpal, short thumb terminal phalanx, cleft lip or palate, along with multiple basal cell carcinomas and skin epidermal cysts, calcified dural folds, keratocysts in the jaws, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, fetal rhabdomyomas were also described [31,131].
Sturge-Weber syndrome manifests with an abnormality in the brain's blood vessels (leptomeningeal angiomatosis), predominantly affecting the posterior parietal and occipital lobes.Common features include MC, facial and choroidal hemangiomata, seizures, and glaucoma [132].
The Sotos and Weaver syndromes, overgrowth syndromes produced by germline mutations in the NSD1 and EZH2 genes, respectively, encode histone methyltransferases and have considerable clinical overlap with MC, giving rise to a high, broad forehead, and prominent chin.Moreover, mostly in Weaver's syndrome, camptodactyly and deep-set nails evolving into a boutonniere deformity in adulthood are reported [19].Malan's syndrome has a similar appearance with MC, a long and narrow triangular face, prognathism, long hands, advanced bone age and scoliosis, and sometimes, aortopathy [20].
Robinow's syndrome may associate MC with frontal bosses, midface hypoplasia and brachydactyly [65,66].Mutations of MED12 on the chromosome X at q13 causes X-linked intellectual disability, with four different phenotypes [137].Of these, in the Lujan-Fryns syndrome, also called X-linked intellectual disability with marfanoid habitus syndrome, MC may be present along with distinct facial dysmorphism, nasal voice, long slender fingers, arachnodactyly, sandal gap, and behavior problems [138].In the Opitz-Kaveggia syndrome, another MED12-associated allelic disease, the clinical features are similar, but the fingers and toes are broad [137].
Some ciliopathies such as the short-rib thoracic dysplasia 8 with or without polydactyly (SRTD8), due to WDR60 mutations, evolve with MC, and give rise to skin changes, along with renal and neurological involvement [30].The rare Adams-Oliver syndrome, a multisystemic disease, may present with or without cutis marmorata telangiectatica congenita and evolves with the scalp and sometimes, skull bone abnormalities and terminal limb defects, including abnormally short fingers and toes with small or absent nails [82].The Cole-Carpenter syndrome is considered a severe form of osteogenesis imperfecta [96].

Congenital Infections
Congenital cytomegalovirus (CMV) infection may affect the CNS and result in HC, temporal cysts, delayed myelination, microcephaly (MiC) or sometimes, MC, with a whole plethora of cerebral or sensorineural abnormalities [63].Associated finger changes may consist of brachydactyly with rudimentary fingernails, finger agenesis, and syndactyly [64,139].
Parvovirus or rubella may result in HC and cerebral vasculitis/vasculopathy [63].

Autoimmune and Autoinflammatory Diseases
HC is rarely described in autoimmune diseases, including systemic lupus erythematosus, juvenile idiopathic arthritis, or systemic sclerosis [140].MC, mainly frontal bossing, and HC may belong to the clinical spectrum of autoinflammatory diseases, mostly in criopyrinopathies such as CINCA/NOMID or Muckle-Wells syndrome [103].Moreover, prominent frontal bossing, triangular face, and hypertelorism are encountered in mevalonate kinase deficiency [104].Urticarial-like and other types of rashes may occur in these diseases.
Fingertip skin lesions including chilblain-like erythema, vasculitis, Raynaud's phenomenon, ulceration, or necrosis may occur in systemic lupus erythematosus or in vasculitis (including in the adenosine deaminase-2 deficiency, DADA2, in which skull involvement is not commonly described) [141].Also, all the above skin lesions, as well as the red scaly lesions suggesting psoriasis, or cold-induced severe ulcerative lesions of fingers, toes, or ears in a child with systemic inflammation may be clinical "red flags" suggesting an interferonopathy [100,142].Many diseases in this group have overlapping clinical features, including the CNS involvement [100].
Interferons (IFNs) are molecules involved in the first defense against pathogens [100].Viral and bacterial pathogens are sensed by pattern recognition receptors, stimulating intracellular pathways with IFN secretion [143].The interferonopathies result either from excessive stimulation, or to defective regulation of the type I IFN pathways [143].
Gain-of-function mutations of IFIH1, encoding the cytosolic double-strand RNA receptor MDA5, results into a heterogeneous spectrum of phenotypes, and chilblain-like lesions, SMS, AGS and SMS/AGS syndromes overlap, while neurologic features and clinical nonpenetrance have been reported within the same family [95,97,109].SMS is an extremely rare sporadic or inherited multisystem disorder with highly variable expression [95,97,109].Typical facial features include high anterior hairline, broad forehead, thin upper vermillion, or smooth philtrum [95].The hands may show acro-osteolysis and/or red, scaly, psoriasis-like rash mainly involving the distal fingers [95].SMS is characterized by dental dysplasia, progressive calcification of the thoracic aorta and main arteries with stenosis, osteoporosis with fractures of the skull, long bones of arms and legs, and expansion of the marrow cavities in the hand and feet bones.Other patients may have delayed growth, abnormal joints ligaments, hips, and feet malformations, generalized muscle weakness or glaucoma [100].The atypical SMS (due to DDX48 mutations) has similar characteristics, but without the dental features [100].AGS, the typical interferonopathy, evolves with an early-onset infectious encephalitis-like syndrome with fever and neuroinflammation, with secondary cerebral atrophy, calcifications, and MiC, but MC and short trunk have also been described [110,143].
MC was also described in 8% of the neonatal lupus erythematosus cases associated with anti-Ro and anti-Ro52 antibodies [114].Tenorio syndrome, a rare overgrowth syndrome evolving with MC and/or large forehead, neurodevelopmental disease, and systemic inflammation, including Sjogren's syndrome features, is due to RNF125 mutations encoding an E3 ubiquitin resulting in dysregulation of several cellular pathways, including that of PI3K-AKT and IFN, respectively [70].MC was also reported with PTEN mutations in lupus, cutaneous vasculitis, and Cowden's syndrome with autoimmune features [115,145,146].Of interest, some RASopathies may also have common pathways with interferonopathies, such as the overgrowth-macrocephaly-facial dysmorphism syndrome, associated with RNF135 mutations encoding Riplet, a co-receptor of the pattern recognition receptor RIG-I [147,148].

Clinical Approach and Therapies
In the presence of MC and the suspicion of an overgrowth syndrome (see Figure 2), apart from a detailed history, physical examination and imaging studies, the approach should include blood analyses, such as IGF-1, thyroid assessment including free T4, TSH, along with assessment of bone age [17].

Clinical Approach and Therapies
In the presence of MC and the suspicion of an overgrowth syndrome (see Figure 2), apart from a detailed history, physical examination and imaging studies, the approach should include blood analyses, such as IGF-1, thyroid assessment including free T4, TSH, along with assessment of bone age [17].Nevertheless, genetic testing plays a pivotal role, with next-generation sequencing (NGS) emerging as a transformative tool.NGS enables the screening of a vast array of genetic variations associated with these syndromes, facilitating precise diagnoses.Therapeutically, management strategies are tailored to individual needs, focusing on addressing specific symptoms and complications.This may encompass a multidisciplinary approach involving neurologists, geneticists, and other specialists to provide comprehensive care.Aside from chromosomal microarray analysis, with the advent of NGS, the ability to identify underlying genetic causes has significantly improved, paving the way for more targeted and effective therapeutic interventions for these complex syndromes.
Genetic testing is paramount in identifying underlying syndromes, keeping in mind that negative testing does not rule out a certain syndrome, mainly in, but not limited to, diseases evolving with mosaicism or with somatic mutations.For instance, in some overgrowth syndromes such as PIK3CA-related overgrowth spectrum (PROs), even advanced genetic testing such as next-generation sequencing may be negative when performed from blood samples, and not from the affected tissue [18].
The existence of reciprocal syndromes where deletions may result in macrocephaly while duplications of the same genomic region may lead to microcephaly is a fascinating aspect of genetic variation.These syndromes underscore the delicate balance of gene dosage and expression in neurodevelopment.Malan syndrome, proximal 19p13.3syndrome, 1q21.1 region anomalies, and NSD1 region aberrations exemplify this phenomenon.Understanding the molecular mechanisms underlying these reciprocal effects can provide important insights into the intricate regulation of brain growth and development.Such knowledge is invaluable for both clinical diagnosis and therapeutic interventions aimed to mitigate the neurological impacts of these genetic alterations.Recognizing a certain disease allows for identification and proactive treatment wherever possible for complications such as an increased cancer susceptibility or others (for instance, Beckwith-Wiedeman Nevertheless, genetic testing plays a pivotal role, with next-generation sequencing (NGS) emerging as a transformative tool.NGS enables the screening of a vast array of genetic variations associated with these syndromes, facilitating precise diagnoses.Therapeutically, management strategies are tailored to individual needs, focusing on addressing specific symptoms and complications.This may encompass a multidisciplinary approach involving neurologists, geneticists, and other specialists to provide comprehensive care.Aside from chromosomal microarray analysis, with the advent of NGS, the ability to identify underlying genetic causes has significantly improved, paving the way for more targeted and effective therapeutic interventions for these complex syndromes.
Genetic testing is paramount in identifying underlying syndromes, keeping in mind that negative testing does not rule out a certain syndrome, mainly in, but not limited to, diseases evolving with mosaicism or with somatic mutations.For instance, in some overgrowth syndromes such as PIK3CA-related overgrowth spectrum (PROs), even advanced genetic testing such as next-generation sequencing may be negative when performed from blood samples, and not from the affected tissue [18].
The existence of reciprocal syndromes where deletions may result in macrocephaly while duplications of the same genomic region may lead to microcephaly is a fascinating aspect of genetic variation.These syndromes underscore the delicate balance of gene dosage and expression in neurodevelopment.Malan syndrome, proximal 19p13.3syndrome, 1q21.1 region anomalies, and NSD1 region aberrations exemplify this phenomenon.Understanding the molecular mechanisms underlying these reciprocal effects can provide important insights into the intricate regulation of brain growth and development.Such knowledge is invaluable for both clinical diagnosis and therapeutic interventions aimed to mitigate the neurological impacts of these genetic alterations.Recognizing a certain disease allows for identification and proactive treatment wherever possible for complications such as an increased cancer susceptibility or others (for instance, Beckwith-Wiedeman syndrome may be associated with hypoglycemia, Malan syndrome with aortopathies, etc.) [17].
The potential therapy largely depends on the identification of the underlying cause.Mechanistically, HC may be treated with shunts.Specific surgical procedures (debulking, ray resection, epiphysiodesis, reconstruction or other surgical procedures have been employed for the correction of overgrowth tissue in the extremities, involving the bone, nerve or fibroadipose tissue [168].
Rehabilitation therapy, with functional improvement or at least preservation, is advisable in all cases.Lhermitte-Duclos syndrome and other diseases evolving with partial ME are treated surgically in selected cases.
In LSDs, where non-degraded substances build up in lysosomes due to mutations in genes encoding lysosomal proteins, the treatment options include the following: enzyme replacement therapy (ERT), substrate reduction therapy (SRT), pharmacological chaperones (PCs), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT).ERT involves administering deficient lysosomal enzymes and has been approved for Gaucher, Fabry, and Pompe diseases, late infantile neuronal ceroid lipofuscinosis type II, acid lipase deficiency, alpha-mannosidosis, and mucopolysaccharidoses (MPS) type I, II, IVA, VI, and VII.SRT inhibits substrate synthesis enzymes.Furthermore, it shows great potential for treating LSDs involving neurological issues, but substantial advancements depend on the ability of new molecules to penetrate the blood-brain barrier (BBB) without disrupting brain lipid levels.PCs target protein misfolding caused by mutations; this medication was first evaluated in Fabry disease, in which the use of α-galactosidase A inhibitors rescued the enzyme activity.PCs have also been evaluated in Gaucher disease, Pompe disease, gangliosidosis (GM1 and GM2), and MPS type II, IIIC, IVA, and IVB.Research continues to discover new PCs meeting specific criteria, including small size, cell permeability, and minimal side effects; many can cross the BBB safely.HSCT involves giving healthy hematopoietic stem cells to patients from various sources like bone marrow, peripheral blood, or umbilical cord blood, and relies on the fact that some lysosomal enzymes can be released into the blood stream and taken up by other cells through specific receptors.HSCT is proposed for several LSDs because it can provide a lifelong source of healthy cells expressing normal enzyme levels.These cells, found in circulating white blood cells and tissue-residing macrophages, can improve or stabilize clinical symptoms, extending life expectancy.In some cases, like MPS I, HSCT is the preferred treatment option and may be more effective if preceded by ERT administration.The effectiveness of GT and gene replacement methods for LSDs has been extensively demonstrated in animal models.The advent of genome editing tools like CRISPR/Cas9, and zinc finger nucleases (ZFN) allows for precise gene targeting and modification.Successful preclinical trials with AAV-mediated ZFN gene therapy have led to phase I/II clinical trials for MPS types I and II.While these trials have confirmed the safety of the technique, clinical observations underscore the need to enhance gene therapy strategies [169].
In many of the diseases involving the major intracellular pathways such as PI3K/AKT/ mTOR, generically called mTORopathies, many therapies are underway [102].Rapamycin and its analogues (rapalogues), oral or topical, have shown significant clinical efficacy in PROs or complex vascular anomalies, although to date the adverse side effects, the lack of specificity, and the incomplete suppression of mTOR targets may hinder their clinical use [102,168].There are ongoing clinical trials targeting intracellular pathways like the PI3K/AKT/mTOR pathway, including sirolimus, miransertib (MK-7075) and alpelisib (BYL719) [168].
Autoimmune and, to some extent, autoinflammatory diseases are being treated, at least in some of their manifestations, with immunosuppressive therapies.In interferonopathies, the anti-IFN therapies may potentially be useful, although many questions have yet to be answered regarding the central role of IFN signaling in these diseases, where non-IFNmediated pathways may be activated as well [170].
There are ongoing research efforts to develop novel therapies for these conditions.The variable responses to treatment make obvious the need for personalized therapeutic approaches in these rare diseases.

Conclusions
From the clinicians' point of view, recognizing a disease or a syndrome may translate into better therapy.Early recognition and timely intervention are paramount to improve outcomes for affected individuals.Understanding the etiology of malformations may aid in the search for modifiable causes of abnormalities [1].An improving knowledge of the cellular and molecular mechanisms bridging skeletal and neural development and inflammation in the developmental disorders will hopefully lead to designing new therapies.Increased awareness, timely recognition, and research could hopefully help the affected children and their families.There are ongoing research efforts aimed at understanding the cellular and molecular mechanisms underlying developmental disorders.Continuous research involving patients and families is very helpful in designing therapies and in improving outcomes.Development of clinical registries such as the Spanish Overgrowth Clinical Registry (SOGRI) may help conduct valuable data collections for advancing research [70].Describing associated features and their possibly common mechanisms could also open the way for research in complex conditions [23].

Figure 1 .
Figure1.The PI3K-AKT pathway, a critical signaling cascade within cells that regulates various cellular processes, including cell cycle, metabolism, proliferation, and survival (image based on[123,124]).Legend: The mTOR (mammalian target of rapamycin) pathway, intersecting with PI3K-AKT, is linked to overgrowth disorders like Proteus syndrome and MCAP (macrocephaly-capillary malformation)

Figure 2 .
Figure 2. A simplified practical approach to the most frequent causes of macrocephaly and finger changes.Legend: ANA-antinuclear antibodies; PTEN-phosphatase and tensin homologue deleted on chromosome 10.

Figure 2 .
Figure 2. A simplified practical approach to the most frequent causes of macrocephaly and finger changes.Legend: ANA-antinuclear antibodies; PTEN-phosphatase and tensin homologue deleted on chromosome 10.

Table 1 .
Upper extremity changes in the context of macrocephaly.

Table 2 .
Causes of macrocephaly with finger changes.