Macrocephaly and Finger Changes: A Narrative Review
Abstract
:1. Introduction
2. Causes of Macrocephaly and Finger Changes
2.1. Skeletal Dysplasias
2.2. Inherited Metabolic Disorders
2.3. Overgrowth Syndromes
2.4. Congenital Infections
2.5. Autoimmune and Autoinflammatory Diseases
3. Clinical Approach and Therapies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACP5: Encoding the tartrate-resistant acid phosphatase 5 |
AD: Autosomal dominant |
AOS: Adams–Oliver syndrome |
AR: Autosomal recessive |
BMP: Bone morphogenetic protein |
BRMUTD: Brain malformations with or without urinary tract defects (BRMUTD) |
CFZS1: Carey–Fineman–Ziter syndrome |
CFC: Cardiofaciocutaneous syndrome |
CINCA/NOMID: Chronic infantile neurologic cutaneous articular syndrome/neonatal-onset multisystem inflammatory disease |
GCPS: Greig cephalopolysyndactyly syndrome |
CPRF: Cleft palate, psychomotor retardation, and distinctive facial feature |
CLAPO syndrome: Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth |
CLOVES syndrome: Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevis, Spinal/Skeletal Anomalies/Scoliosis |
CMDR: Craniometaphyseal dysplasia, autosomal recessive |
CMV: Cytomegalovirus |
CNS: Central nervous system |
CNVs: Copy number variations |
COGIS: Cohen–Gibson syndrome |
DADA2: Adenosine deaminase-2 deficiency |
DDVIBA: Developmental delay with variable impairment and behavioral abnormalities |
EDHHACC: Ectodermal dysplasia, hyperhidrotic with hypothyroidism and agenesis of the corpus callosus |
EGF: Epidermal growth factor |
ERT: Enzyme replacement therapy |
FB: Frontal bossing |
FCAS: Familial cold-induced autoinflammatory syndrome |
FGFR: Fibroblast growth factor receptors |
GAGs: Glycosaminoglycans |
GT: Gene therapy |
HC: Hydrocephalus |
HMEG: Hemimegaloencephaly |
HSCT: Hematopoietic stem cell transplantation |
ID: Intellectual disability |
IGF-I: Insulin-like growth factor I |
IHH-PTHrP: IHH (Indian Hedgehog), which stimulates PTH-related protein pathway |
JIA: Juvenile idiopathic arthritis |
LSDs: Lysosomal storage disorders |
MC: Macrocephaly |
MCAP: Macrocephaly-capillary malformation |
ME: Megalencephaly |
MDFPMR: Macrocephaly, dysmorphic facies, and psychomotor retardation |
MiC: Microcephaly |
MNKES: Muenke craniosynostosis syndrome |
MPPH: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome |
MPPM: Megalencephaly-polymicrogyria-pigmentary mosaicism |
MPS: Mucopolysaccharidoses |
mTOR: Mammalian target of rapamycinNGS: next-generation sequencing |
NS: Noonan syndrome |
OMIM: Online Mendelian Inheritance in Man |
PBD: Peroxisome Biogenesis Disorders |
PCs: Pharmacological chaperones |
PHTS: PTEN Hamartoma-tumor syndrome |
PRAAS: Proteasome-associated autoinflammatory syndromes |
PROS: PIK3CA-related overgrowth spectrum |
PTEN: Phosphatase and tensin homologue deleted on chromosome 10 |
SAVI: STING associated vasculopathy with onset in infancy |
SGMRT: Singleton-Merten syndrome |
SHH: Sonic hedgehog (pathway) |
SIHIWES: Sifrim–Hitz–Weiss syndrome |
SOGRI: Spanish Overgrowth Clinical Registry |
SPENCD: Spondyloenchondrodysplasia |
SRT: Substrate reduction therapy |
SRTD8: Short-rib thoracic dysplasia 8 with or without polydactyly |
STING: Stimulator of Interferon Genes |
TBRS: Tatton–Brown–Rahman syndrome |
THES: Trichohepatoenteric syndrome |
TSC1, TSC2: Tuberous sclerosis complex 1, Tuberous sclerosis complex 2 |
TSH: thyroid-stimulating hormone |
UPD: Uniparental disomy |
VEGF: Vascular endothelial growth factor |
XL: X-linked disorder |
XLD: X-linked dominant disorder |
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Upper Extremity Changes | Syndromes | Head Enlargement Type | References |
---|---|---|---|
Polydactyly | VACTERL-H syndrome | MC | [28] |
Apert syndrome | MC | [29] | |
Short-rib thoracic dysplasia 8 | MC | [30] | |
Bardet–Biedl syndrome | MC | [30] | |
Gorlin syndrome | MC, HC, FB | [31,32,33,34,35] | |
GCPS | MC | [36] | |
Acro-callosal syndrome | MC | [37] | |
Joubert syndrome 2 | MC, FB | [38] | |
Oligodactyly | VACTERL-H syndrome | MC | [28] |
Digit malposition | BRMUTD (First finger insertion) | MC, HC | [39] |
Finger tapering | Turnpenny—Fry syndrome | FB | [40] |
Sifrim–Hitz–Weiss syndrome | MC | [41] | |
Carey–Fineman–Ziter syndrome | MC | [42] | |
Camptodactyly | Osteopathia striata with cranial sclerosis | MC | [43] |
MC | [19] | ||
Sotos syndrome | MC | [19,44] | |
Weaver syndrome | MC | [45,46] | |
Cohen–Gibson syndrome | MC | [47] | |
Rahman syndrome | MC | [48] | |
Alcuraya–Kucinskas syndrome | MC | [38] | |
Joubert syndrome 2 | MC, FB | [49,50,51,52] | |
Trichohepatoenteric syndrome | FB | [49,50,51,52] | |
Clinodactyly | Keipert syndrome | MC | [53] |
Osteopathia striata with cranial sclerosis | MC | [43] | |
Peroxisome biogenesis disorder (Zellweger syndrome) | MC | [54,55] | |
DDVIBA | MC | [56] | |
Muenke craniosynostosis syndrome | MC | [57,58] | |
Silver–Russel syndrome | MC | [59] | |
SOFT syndrome | MC | [60] | |
Larsen-like syndrome | MC | [61] | |
CPRF | MC, FB | [48] | |
Alcuraya–Kucinskas syndrome | MC | [62] | |
Desmosterolosis | MC, FB | [42] | |
Brachydactyly | Congenital CMV infection | MC | [63,64] |
Robinow syndrome | MC | [65,66] | |
Beta thalassemia | MC | [67,68] | |
Pycnodysostosis | MC | [69] | |
Pfeiffer syndrome | MC | [23] | |
Gorlin syndrome | MC, FB | [31,32,33,34,35] | |
Keipert syndrome | MC | [53] | |
Simpson–Golabi–Behmel | MC | [70,71] | |
Muenke craniosynostosis syndrome | MC | [57] | |
SOFT syndrome | MC | [59] | |
Temtamy syndrome | MC, FB | [72] | |
Retinitis pigmentosa with or without skeletal anomalies | MC, FB | [42] | |
Syndactyly | VACTERL-H syndrome | MC | [28] |
Pfeiffer syndrome | MC | [23] | |
Apert syndrome | MC, ME | [29] | |
Gorlin syndrome | MC | [31,32,33,34,35] | |
Simpson–Golabi–Behmel (second to third fingers) | MC | [73] | |
GCPS (cutaneous syndactyly) | MC | [36] | |
Arachnodactyly | MDFPMR | MC, FB | [74,75,76] |
EDHHACC | MC, FB | [77] | |
Divergent fingers | Achondroplasia (trident hand) | MC | [3] |
CLOVES syndrome (wide spacing between digits) | MC, ME | [78,79] | |
Digital webbing | Pfeiffer syndrome | MC | [23] |
Apert syndrome | MC, ME | [29] | |
Polyphalangy | VACTERL-H syndrome (triphalangeal thumb) | HC | [28] |
Osteopathia striata with cranial sclerosis | MC | [43] | |
Broad terminal phalanges (spatulate fingers) | Keipert syndrome | MC | [53] |
Osteopathia striata with cranial sclerosis | MC | [43] | |
Costello syndrome | MC | [80] | |
Phalangeal hypoplasia | Robinow syndrome | MC | [65,66] |
Joubert syndrome | MC | [30] | |
Gorlin syndrome (First finger) | MC, HC, FB | [31,32,33,34,35] | |
Smith–Kingsmore syndrome | MC, FB | [81] | |
Simpson–Golabi–Behmel syndrome | MC | [73] | |
Adams–Oliver syndrome | MC, HC | [82] | |
Retinitis pigmentosa with or without skeletal anomalies | MC, FB | [42] | |
Phalangeal form changes | Mucopolysaccharidoses are bullet-shaped (proximal pointing) | MC, HC | [83,84,85,86] |
Muenke craniosynostosis syndrome (thimble-like middle phalanges) | |||
MC | [57] | ||
Brachymetacarpia (short metacarpal or metatarsal) | Noonan syndrome 2 (fifth finger) | MC | [87,88] |
Gorlin syndrome (fourth finger) | MC, HC, FB | [31,32,33,34,35] | |
Pelger–Huet anomaly | MC | [89,90] | |
Bone changes | |||
Radial hypo/aplasia | VACTERL-H syndrome | HC | [28] |
Radioulnar synostosis | VACTERL-H syndrome | HC | [28] |
Ulnar deviation | Peroxisome biogenesis disorder (Zellweger syndrome) | MC | [54,55] |
Costello syndrome | MC | [80] | |
Bone sclerosis | Craniometaphyseal dysplasia AR | MC | [91] |
Dysostosis multiplex | Mucopolysaccharidoses | MC, HC | [83,84,85,86] |
Skeletal dysplasia | SPENCDI | MiC/MC/FB | [70,92,93,94,95] |
Singleton–Merten syndrome | MiC/MC/FB | ||
Enchondromas | SPENCDI | MiC/MC/FB | [92,93,94] |
Acroosteolysis | Picnodysostosis | MC | [69] |
Cole–Carpenter syndrome | HC, FB | [96] | |
Singleton–Merten syndrome | MiC/MC/FB | [95,97] | |
Joint changes | |||
Joint contractures | Mucopolysaccharidosis | MC, HC | [83,84,85,86] |
Gangliosidosis type I | MC | [8,98] | |
Peroxisome biogenesis disorder (Zellweger syndrome) | MC | [54,55] | |
Noonan syndrome type 2 | MC | [87,88] | |
L1 syndrome | HC | [99] | |
Desmosterolosis | MC | [48] | |
Carey–Fineman–Ziter | MC | [42] | |
Singleton–Merten syndrome | MiC/MC, FB | [95,100,101] | |
Joint hypermobility | Osteogenesis imperfecta | MC | [96] |
Osteopathia striata with cranial sclerosis | MC, FB | [43] | |
Pycnodysostosis | MC | [69] | |
Pretzel syndrome | ME | [102] | |
Cohen–Gibson syndrome | MC | [45,46] | |
Tatton–Brown–Rahman syndrome | MC | [17] | |
MDFPMR | MC, FB | [74,75,76] | |
Small joint arthritis | Cryopyrinopathies: CINCA/NOMID, Muckle–Wells etc. | FB, HC | [103] |
MVK deficiency | FB | [104] | |
Beta-thalassemia | MC | [67,68] | |
Villonodular synovitis, multiple sites | Noonan syndrome | MC | [105,106] |
Carpal tunnel syndrome | Mucopolysaccharidoses | MC, HC | [83,84,85,86] |
Nail changes | |||
Nail dystrophy | Nail-patella syndrome | MC | [98] |
Robinow syndrome | MC | [65,66] | |
Costello syndrome | MC | [80] | |
Adams–Oliver syndrome | MC, HC | [82] | |
SOFT syndrome | MC | [59] | |
Primrose syndrome | MC | [61] | |
Single nail common to more digits | Apert syndrome | MC, FB, ME | [29] |
Skin changes | |||
Thickened skin | Gangliosidosis type I | MC | [8,98] |
Dry, hyperkeratotic skin | Cardiofaciocutaneous syndrome | MC | [107] |
Wrinkled skin | Costello syndrome | MC | [80] |
Pitted hands | Gorlin syndrome | MC, HC, FB | [31,32,33,34,35] |
Deep palmar creases | Smith–Kingsmore syndrome | MC | [81] |
Single palmar creases | Adams–Oliver 2 syndrome | MC | [108] |
Vascular, lymphatic, and other changes | |||
Finger necrosis/amputation | Interferonopathies | MiC/MC, FB | [109,110,111,112] |
Acrocyanosis | Congenital heart disease | MC | [113] |
Aicardi–Goutières | MC/MiC | [111,112] | |
Hand and feet edema | Mucopolysaccharidosis VI | MC | [83,84,85,86] |
Noonan syndrome | MC | [105,106] | |
Raynaud’s phenomenon | Neonatal SLE | MC | [114,115] |
Interferonopathies | MiC/MC | [109,110] | |
Soft tissue masses | PROS | MC, HC, FB | [31,32,33,34,35] |
Disease | Inheritance | Causes/Mutations | Main Craniofacial and Hand/Finger Changes | References |
---|---|---|---|---|
Acquired conditions | ||||
Rickets | Vitamin D deficiency | MC, FB, broad front, delayed closure of fontanelles, craniotabes, thickened wrists | [3] | |
Congenital infection | Cytomegalovirus infection | HC, cortical development abnormalities, brachydactyly | [63,64] | |
Bone marrow disorders | ||||
Beta-thalassemia OMIM # 613985 | AR (AD) | HBB | Prominent frontal and maxillary bones, sausage-like digits, small joints arthritis, fractures, signs of hypovitaminosis D | [67,68] |
Congenital cyanotic heart diseases | MC with “hair-on-end” radiological skull changes, acrocyanosis | [113] | ||
Skeletal dysplasias | ||||
Achondroplasia OMIM # 100800 | AD | FGFR3 | MC, short fingers with divergent ring and middle fingers (trident hand) | [98] |
Pycnodysostosis OMIM # 265800 | AR | CTSK | MC, acro-osteolysis of the terminal phalanges, short fingers, joint hypermobility | [69] |
Cole–Carpenter syndrome | AR | P4HB | HC, frontal bossing, craniosynostosis, ocular proptosis, frequent fractures, wide metacarpal and phalangeal epiphyses, cystic appearance, acro-osteolysis | [96] |
VACTERL-H, VACTERL association, X-linked, with or without hydrocephalus; VACTERLX, OMIM # 314390 | XLR | SHH signaling, GLI3 TBX-SALL4-SALL1-WNT pathway FGF8-FGF10 pathway | HC, radial hypo/aplasia, triphalangeal thumb, polydactyly, oligodactyly, syndactyly, radioulnar synostosis | [28,149,150] |
Robinow syndrome OMIM # 268310 | AR/AD | ROR2, WNT5A, DVL1, DVL3 | MC, FB, limb shortening, brachydactyly, phalangeal and nail hypoplasia | [65,66] |
Osteopathia striata with cranial sclerosis (OSCS) OMIM # 300373 | XLD | AMER1 | MC, FB, long, slender fingers, fifth finger clinodactyly, camptodactyly, finger contractures, duplicate phalanges, spatulate distal phalanges | [43] |
Pfeiffer syndrome, OMIM # 101600 | AD | FGFR1 FGFR2 | Cloverleaf skull, high forehead, syndactyly, brachydactyly, digital webbing | [23] |
Apert syndrome OMIM # 101200 | AD | FGFR2 | ME, high, broad forehead, single nail common to digits 2 to 4, symmetric osseous and/or cutaneous syndactyly, polydactyly | [29] |
Muenke craniosynostosis Syndrome (MNKES), OMIM # 602849 | AD | FGFR3 | MC, plagiocephaly, brachycephaly, premature suture closure, midface retrusion, hypertelorism, clinodactyly, brachydactyly, mild hand and feet anomalies | [23] |
Craniometaphyseal dysplasia, autosomal recessive (CMDR) OMIM #218400 | AR | GJA1 | MC, coarse facial features, metacarpal and phalangeal sclerosis | [91] |
Osteogenesis Imperfecta type X | AR | SERPINH1 | MC, high forehead, triangular face, midface hypoplasia, hyperextensibility of the fingers | [151] |
Keipert syndrome OMIM # 301026 | XLR | GPC4 | MC, hypertelorism, flat midface, prominent lips, brachydactyly, clinodactyly, broad terminal phalanges | [53] |
Craniometaphyseal dysplasia, autosomal recessive (CMDR) OMIM #218400 | AR | GJA1 | MC, coarse facial features, metacarpal and phalangeal sclerosis | [91] |
Ciliopathies | ||||
Short-rib thoracic dysplasia 8 with or without polydactyly (SRTD8) OMIM # 615503 | AR | WDR60 | MC, polydactyly, skin changes | [30] |
Bardet–Biedl syndrome OMIM # 617119 | AR | IFT74 | MC (or MiC), polydactyly | [30] |
Joubert syndrome OMIM # 213300 | AR | INPP5E | MC, prominent forehead, high rounded eyebrows, missing digital phalanges | [30] |
Inherited metabolic disorders | ||||
Mucopolysaccharidoses MPS I (Hurler syndrome) OMIM # 607014 MPS II (Hunter syndrome), OMIM # 309900 MPS VI (Maroteaux-Lamy), OMIM # 253200 MPS VII (Sly syndrome), OMIM # 253220 | MPS I: AR, MPS II: X-linked, MPS VI: AR, MPS VII: AR | MPS I: IDUA MPS II: IDS MPS VI: ARSB, MPS VII: GUSB | MPS I: large head with bulging frontal bones (MC, HC), carpal tunnel syndrome with weakness in the hand and fingers, phalanges are bullet-shaped with proximal pointing of the second to fifth metacarpals. MPS II: MC, claw hands, stiffness, joint contractures, carpal tunnel syndrome, joint hypermobility, dysostosis multiplex. MPS VI: coarse dysmorphic features, HC, edema of the hands and feet, dysostosis multiplex. MPS VII (mild form): MC, mild craniofacial dysmorphism, dysostosis multiplex | [83,84,85,86] |
Gangliosidosis type I OMIM # 230500 | AR | GLB1 | MC, claw hands, thickened subcutaneous tissues | [8,98] |
Alpha-mannosidosis type I (Hurler-like disease) OMIM # 248500 | AR | MAN2B1 | HC, large head with prominent forehead, dysostosis multiplex | [152] |
Peroxisome biogenesis disorder (cerebrohepatorenal/ Zellweger syndrome) OMIM # 214100 | AR | PEX1, PEX3, PEX6, PEX16, PEX2, PEX12, PEX14, | MC (or MiC), dysmorphic features (large anterior fontanel, prominent high forehead), finger flexion; long fingers, deviated to the ulnar side, the thumbs were not held in apposition | [54,55] |
RASopathies | ||||
Costello syndrome OMIM # 218040 | AD | HRAS | Coarse facies, wrinkled skin, splayed spatulate fingers, abnormal nails, ulnar deviation | [80] |
Cardio-facio-cutaneous syndrome OMIM # 115150 | AD | BRAF, MAP2K1, MAP2K2, KRAS | Joint contractures, dry, hyperkeratotic scaly skin, ulnar deviation, deep palmar creases | [107] |
Noonan syndrome (NS) NS 1, OMIM # 163950 NS 3, OMIM # 609942 NS 4, OMIM # 610733 NS 5, OMIM # 611553 NS 6, OMIM # 613224 | AD | PTPN11, KRAS, SOS1, RAF1, NRAS, | Broad forehead, dolichocephaly, polyarticular pigmented villonodular synovitis, peripheral lymphedema | [105,106] |
Noonan syndrome (NS) 2 OMIM # 605275 | AR | LZTR1 | Broad forehead, fifth brachymetapody, arthrogryposis | [87,88] |
Overgrowth syndromes | ||||
Gorlin–Goltz syndrome/ Gorlin syndrome/ [Nevoid basal cell carcinoma syndrome (NBCCS)] OMIM # 109400 | AD | PTCH1 | MC/ relative MC, mild HC, FB, pitted hands, brachydactyly, short fourth metacarpal, polydactyly, 2–3 syndactyly, short thumb terminal phalanx | [31,32,33,34,35] |
PTEN hamartoma tumor syndrome: Cowden’s syndrome, Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos syndrome OMIM # 158350 | AD | PTEN | MC/ME, HC, asymmetric soft-tissue masses, increased fat deposition, enlarged vessels MC/ME, HC, cerebellar signs, papilledema | [133] [134] |
Smith–Kingsmore syndrome (SKS), Minds syndrome OMIM # 616638 | AD | MTOR | MC, FB, tall forehead, midface hypoplasia, short proximal and distal phalanges, deep palmar creases | [81] |
CLOVES syndrome, OMIM # 612918 Proteus syndrome, OMIM # 176920 MCAP syndrome, OMIM # 602501 MPPH syndrome 1 OMIM # 603387 | AD, somatic mutations, arise randomly in one cell during embryonic development | PI3K/AKT/mTOR pathway (CCND2, PIK3R2, AKT3, PIK3CA, MCC, NSD1) | MC, ME and capillary malformations, asymmetric overgrowth of the extremities, wide spacing between digits, lymphatic anomalies | [78,79] |
Sotos syndrome OMIM # 117550 | AD | NSD1 | MC, high broad forehead, long face, prominent chin, advanced bone age, camptodactyly | [19] |
Weaver syndrome OMIM # 277590 | AD | EZH2, NSD1 | MC, camptodactyly of the fingers and/or toes, hyperextensibility of the fingers, finger contractures, thin, deep-set nails, boutonniere deformity in adults | [19,44,153] |
Malan syndrome OMIM # 277590 | AD | NFIX | MC, long and narrow triangular face, prognathia, aortopathy, advanced bone age, scoliosis, long hands, ID | [20] |
* Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome, Pretzel syndrome (PMSE) OMIM # 611087 | AR | STRAD-alpha (LYK5) | ME, cognitive delay, hyperextensible fingers | [102] |
Simpson–Golabi–Behmel syndrome (SGBS1) OMIM # 312870 | X-linked | GPC3, GPC4 | MC, pre- and postnatal overgrowth, coarse facies, index finger hypoplasia, syndactyly second to third fingers, brachydactyly, broad hands, polydactyly | [70,71,73] |
Cohen–Gibson syndrome (COGIS) OMIM # 617561 | AD | EED | MC, broad forehead, long fingers, broad thumbs, camptodactyly, joint laxity of the small joints of the hand | [45,46] |
Rahman syndrome (RMNS) OMIM # 617537 | AD | HIST1H1E (H1-4) | Increased height and/or head circumference early in life, camptodactyly | [47] |
Tatton–Brown–Rahman syndrome (TBRS) OMIM #615879 | AD | DNMT3A | MC, round facies, bushy eyebrows, prominent maxillary incisors, joint hyperlaxity | [17] |
Intellectual developmental disorder with hypertelorism and distinctive facies OMIM # 618147 | AD | CCNK | MC, high anterior hairline, tapered fingers | [154] |
Brain malformations with or without urinary tract defects (BRMUTD) OMIM # 613735 | AD | NFIA | MC, ventriculomegaly, overgrowth, bilateral proximally placed first fingers | [39] |
Developmental Delay with Variable Intellectual Impairment and Behavioral Abnormalities (DDVIBA) OMIM # 618430 | AD | TCF20 | MC, brachycephaly, FB, Tapering fingers, fifth finger clinodactyly | [56] |
Other inherited causes | ||||
L1 syndrome OMIM # 307000 | XLR | L1CAM | HC, arthrogryposis, adducted thumbs, developmental delay | [99] |
Adams–Oliver syndrome (AOS1) OMIM # 100300 | AD/ AR | NOTCH1, ARHGAP31, DOCK6, EOGT, DLL4, or RBPJ | Encephalocele, ventriculomegaly, slight ventricular dilation, periventricular leukomalacia, short or missing phalanges, dysplastic or absent nails | [82] |
Adams–Oliver syndrome-2 (AOS2) OMIM # 614219 | AR | DOCK6 | MC (or MiC), mild facial dysmorphism, low hair line, shortened digits, single palmar creases | [108] |
Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) OMIM # 617011 | AR | HERC1 | MC, FB, somatic overgrowth apparent at birth, seizures, joint laxity, and long fingers; large hands with arachnodactyly | [74,75,76] |
Silver–Russell Syndrome OMIM # 180860 | hypomethylation on ch. 11p15.5 or maternal UPD for ch. 7 | IGF2, CDKN1C, PLAG1, HMGA2, H19 | FB or prominent forehead, fifth finger clinodactyly | [58] |
Turnpenny–Fry syndrome OMIM # 618371 | AD | PCGF2 | FB, short tapering fingers | [40] |
Greig cephalopolysyndactyly syndrome (GCPS)OMIM # 175700 | AD | GLI3 | MC, high, prominent forehead, preaxial polydactyly, abnormally wide thumb or big toe, cutaneous syndactyly | [36] |
Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT syndrome)OMIM # 614813 | AR | POC1A | MC (present during early childhood), protruding forehead, short rectangular fingers and hypoplastic fingernails, clinodactyly, brachydactyly | [59] |
Acro-callosal Syndrome (ACLS), Joubert syndrome 12, OMIM # 200990 | AR | KIF7 | MC, prominent forehead, postaxial polydactyly of the hands, and preaxial polydactyly of the feet | [37] |
Intellectual developmental disorder, X-linked syndromic, Cabezas type OMIM # 300354 | XLR | CUL4B | MC/relative MC, short thumbs, and little fingers with adduction, brachydactyly | [155] |
Ectodermal Dysplasia, Hypohidrotic, with Hypothyroidism and Agenesis of The Corpus Callosum OMIM # 225040 | may be XL | may represent a contiguous gene syndrome | MC, FB, long slender fingers | [77] |
Primrose syndrome (PRIMS) OMIM # 259050 | AD | ZBTB20 | MC, dystrophic/abnormal fingernails, and toenails | [61] |
Larsen-like syndrome OMIM # 608545 | Isolated cases | location: 6p25 | MC, brachycephaly, prominent forehead, cylindrical fingers, clinodactyly (fourth and fifth fingers) | [60] |
Cleft palate, psychomotor retardation, and distinctive facial feature (CPRF) OMIM # 616728 | AD | KDM1A | MC (in some patients), brachycephaly, FB, tapered fingers, fifth finger clinodactyly, short thumbs | [156] |
Chromosome 5p13 duplication syndrome OMIM # 613174 | Isolated cases | microduplications 5p13 | MC, turricephaly, FB, broad forehead, large hands, long fingers | [157] |
Phelan–McDermid syndrome (PHMDS) OMIM # 606232 | AD | SHANK3 | MC, dolichocephaly, asymmetric face, dysplastic toenails | [158] |
Sifrim–Hitz–Weiss syndrome (SIHIWES) OMIM # 617159 | AD | CHD4 | MC, trigonocephaly, coarse facies, tapered fingers, fusion of the wrist bones | [41] |
Alkuraya–Kucinskas syndrome (ALKKUCS) OMIM # 617822 | AR | KIAA1109 | MC, plagiocephaly, overlapping fingers, camptodactyly, clenched hands adducted thumbs, clinodactyly | [48] |
Desmosterolosis OMIM # 602398 | AR | DHCR24 | MC relative (sometimes microcephaly), FB, arthrogryposis, fifth finger clinodactyly, | [62] |
Wiedemann–Rautenstrauch syndrome (WDRTS) OMIM #264090 | AR | POLR3A | MC/relative MC, FB, triangular face, long fingers, large hands | [159] |
Joubert syndrome 2 (JBTS2) OMIM # 608091 | AR | TMEM216 | MC, dolichocephaly, FB, postaxial polydactyly, camptodactyly | [38] |
Temtamy syndrome (TEMTYS) OMIM #218340 | AR | C12ORF57 | MC, FB, long face, brachydactyly (second to fifth fingers), bulbous thumbs | [72] |
Carey–Fineman–Ziter syndrome (CFZS1) OMIM # 254940 | AR | MYMK | MC, (sometimes microcephaly), plagiocephaly, tapering fingers, distal contractures | [42] |
Retinitis pigmentosa with or without skeletal anomalies OMIM #250410 | AR | CWC27 | MC (in some patients), FB, brachydactyly, shortening of distal phalanges | [160] |
Pelger–Huet anomaly OMIM #169400 | AD | LBR | MC with prominent forehead, short metacarpals in several fingers | [89,90] |
Fragile X syndrome, OMIM # 300624 | XLD | FMR1 | MC, coarse facies, large forehead, long face prominent jaw, hyperextensibility finger joints, dermatoglyphic findings, double-jointed thumbs | [161,162,163,164] |
Spinocerebellar ataxia, autosomal recessive 20, OMIM # 616354 | AR | SNX14 | Relative MC, clinodactyly, camptodactyly, brachydactyly | [165] |
Autoimmune | ||||
Systemic lupus erythematosus | MC in 8% neonatal SLE, HC; Raynaud’s phenomenon, vasculitis, rashes | [114,115] | ||
Juvenile idiopathic arthritis | HC (rarely); small joints arthritis | [140] | ||
Systemic sclerosis | HC (rarely), Raynaud’s phenomenon, sclerodactyly | [140]. | ||
Autoinflammatory | ||||
Cryopyrinopathies [CINCA/NOMID (OMIM # 607115), Muckle-Wells (OMIM # 191900), FCAS (OMIM # 120100)] | AD | NLRP3 | Urticarial-like rashes, aseptic meningitis, FB, MC, oligoarthritis | [103] |
* Mevalonate kinase deficiency (MVK, mevalonic aciduria, hyper IgD syndrome) OMIM # 610377 | AR | MVK | FB, dolichocephaly, triangular facies; rash, edema and arthralgia may occur during febrile crisis | [104] |
Spondyloenchondrodysplasia with immune features OMIM # 607944 | AR | ACP5 | Cranio-facial deformities, hand anomalies, enchondromas | [92,93,94] |
Aicardi–Goutières syndrome (AGS) AGS1: OMIM # 225750 AGS2: OMIM # 610181 AGS3: OMIM # 610329 AGS4: OMIM # 610333 AGS5: OMIM # 612952 AGS6: OMIM # 615010 AGS7: OMIM # 615846 AGS8: OMIM # 619486 AGS9: OMIM # 619487 | AD (for several cases with TREX1gene mutation), AR | TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH-1, LSM11, RNU7-1 | MiC/MC, pseudo-TORCH syndrome, dysmorphic features; acrocyanosis, autoamputation of the fingers, chilblain-like lesions | [109,110,111,112] |
Singleton–Merten syndrome (SGMRT) OMIM # 182250 | AD | IFIH1 | Broad forehead, high hairline, acro-osteolysis, skeletal dysplasia, aortic calcifications, psoriasis, glaucoma | [95,97] |
* Atypical Singleton–Merten syndrome SGMRT2, OMIM # 616298 | AD | DDX58 | Similar to SGMRT1, arthritis of the hands, metacarpophalangeal contractures; possibly calcified ligaments of the interphalangeal and metacarpophalangeal joints, mild distal erosions | [95,100,101] |
* Tenorio syndrome OMIM # 616260 | AD | RNF125 | MC, overgrowth, large forehead, mild HC, Sjogren’s syndrome features | [70] |
USP18 deficiency, OMIM # 617397 | AR | USP18 | Pseudo-TORCH syndrome 2; HC, brain malformation, metaphyseal X-ray changes resembling intrauterine infections | [142,144,166,167] |
* Trichohepatoenteric syndrome (THES) THES1: OMIM # 222470 THES2: OMIM # 614602 | AR | TTC37 (SKIC3) SKIV2L (SKIC2) | Prominent forehead and cheeks, broad nasal root, trichorrhexis nodosa, skin changes, diarrhea; café-au-lait spots on the lower limbs, camptodactyly | [49,50,51,52,142] |
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Lazea, C.; Vulturar, R.; Chiș, A.; Encica, S.; Horvat, M.; Belizna, C.; Damian, L.-O. Macrocephaly and Finger Changes: A Narrative Review. Int. J. Mol. Sci. 2024, 25, 5567. https://doi.org/10.3390/ijms25105567
Lazea C, Vulturar R, Chiș A, Encica S, Horvat M, Belizna C, Damian L-O. Macrocephaly and Finger Changes: A Narrative Review. International Journal of Molecular Sciences. 2024; 25(10):5567. https://doi.org/10.3390/ijms25105567
Chicago/Turabian StyleLazea, Cecilia, Romana Vulturar, Adina Chiș, Svetlana Encica, Melinda Horvat, Cristina Belizna, and Laura-Otilia Damian. 2024. "Macrocephaly and Finger Changes: A Narrative Review" International Journal of Molecular Sciences 25, no. 10: 5567. https://doi.org/10.3390/ijms25105567