The small bones and soft tissues of the hands and feet can be affected by systemic disorders, and frequently, the findings are quite unique and virtually diagnostic for some genetic or metabolic disorders.
Materials and Methods
Photographs and imaging studies for the hands and feet are available in a digitized system, which has been approved by our hospital institutional review board. Examination of these and their description can establish a relationship with some degree of certainty to a series of highly variable and uncommon clinical disorders.
Results
Description of the clinical, physiologic and genetic characteristics, and illustrations of hand and foot abnormalities are provided for an array of diseases, including Ellis–van Creveld syndrome, fibrodysplasia ossificans progressiva, achondroplasia, Kniest dysplasia, pseudo- and pseudopseudohypoparathyroidism, acromegaly, nail–patella syndrome, Marfan's disease, cartilage–hair hypoplasia, and several forms of mucopolysaccharidosis.
Conclusions
The findings support the concept that many genetic disorders can often be diagnosed by clinical and imaging examination of the patient's hands and feet.
AgarwalCSeigleRAgarwalS. Pseudohypoparathyroidism: a rare cause of bilateral slipped capital femoral epiphysis. J Pediatr.2006;149:406–8.
2.
AhnNUSponsellerPDAhnUM. Dural ectasia is associated with back pain in Marfan syndrome. Spine.2000;25:1562–8.
3.
AlbrightFBurnettCHSmithPH. Pseudohypoparathyroidism: an example of “Seabright-Bantam syndrome”. Endocrinology.1942;30:922–32.
4.
AlbrightFForbesAPHennemanPH. Pseudopseudohypoparathyroidism. Trans Assoc Am Physicians.1952;65:337–50.
5.
AsaSLEzzatS. Genetics and proteomics of pituitary tumors. Endocr.2005;28:43–7.
6.
AshworthJLBiswasSWraithELloydIC. Mucopolysaccharidoses and the eye. Surv Opthalmol.2006;51:1–17.
7.
BachGFriedmanRWeissmanBNeufieldEF. The defect in the Hurler and Scheie syndromes: deficiency of alpha-l-iduronidase. Proc Natl Acad Sci USA.1972;69:2048–51.
8.
BaileyJAII. Orthopaedic aspects of achondroplasia. J Bone Jt Surg.1970;52A:1285–301.
9.
BannaM. Compressive meningeal hypertrophy in mucopolysaccharidoses. Am J Neuroradiol.1987;8:385–6.
10.
BarkanAL. Acromegaly: diagnosis and therapy. Endocrinol Metab Clin North Am.1989;18:277–310.
BeightonP. Fibrodysplasia ossificans progressiva. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St. Louis: Mosby; 1993. p. 501–18.
13.
BesserGMMortimerCHCarrD. Growth hormone release inhibiting hormone in acromegaly. Br Med J.1974;1:352–5.
14.
BoileauCJondeauGMizuguchiTMatsumotoN. Molecular genetics of Marfan syndrome. Curr Opin Cardiol.2005;20:194–200.
15.
BonafeLSchmittKEichG. RMRP gene sequence analysis confirms a cartilage–hair variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet.2002;61:146–51.
16.
BongersEMGublerMCKnoersNV. Nail–patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol.2002;17:703–12.
17.
BongersEMHuysmansFTLevtchenkoE. Genotype–phenotype studies in nail patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet.2005;13:935–46.
18.
BrillPWKimHJBerattsNGHirschhornK. Skeletal abnormalities in the Kniest syndrome with mucopolysacchariduria. Am J Roentgenol Radium Ther Nucl Med.1975;125:731–8.
19.
BrookeAMDrakeWM. Serum IGF-I levels in the diagnosis and monitoring of acromegaly. Pituitary.2007;10:173–9.
20.
CahuanaAPalmaCGonzalesWGeanE. Oral manifestations in Ellis–van Creveld syndrome: report of five cases. Pediatr Dent.2004;26:277–82.
21.
CenturionSASchwartzRA. Cutaneous signs of acromegaly. J Dermatol.2002;41:631–4.
22.
ChalamKVTripathiRCTripathiBJ. Cataract in Kniest dysplasia: clinicopathologic correlation. Arch Ophthalmol.2004;122:913–15.
23.
ChenLYangWColeWG. Alternative splicing of exon 12 of the COL2A1 gene interrupts the triple helix of type–II collagen in the Kniest form of spondyloepiphyseal dysplasia. J Orthop Res.1996;14:712–21.
24.
ChoJYGuoCTorelloM. Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia. Proc Natl Acad Sci USA.2004;101:609–14.
25.
ClearyMAWraithJE. The presenting features of mucopolysaccharidosis type IH (Hurler Syndrome). Acta Paediatr.1995;84:337–9.
26.
ClemmonsDR. Quantitative measurement of IGF-I and its use in diagnosing and monitoring treatment of disorders of growth hormone secretion. Endocr Dev.2005;9:55–65.
27.
ColaoAFeroneDMarzulloPLombardiG. Systemic complications of acromegaly: epidemiology, pathogenesis and management. Endocrinol Rev.2004;25:102–52.
28.
ColaoAPivonelloRMarzulloP. Severe systemic complications of acromegaly. Endocrinol Invest.2005;28(5 Suppl):65–77.
29.
ColeWG. Abnormal skeletal growth in Kniest dysplasia caused by type II collagen mutations. Clin Orthop.1997;341:182–9.
30.
ConnorJMEvansDA. Fibrodysplasia ossificans progressiva: clinical features and natural history of 34 patients. J Bone Jt Surg.1982;64:76–83.
31.
CoupeRLLowryRB. Abnormality of the hair in cartilage–hair hypoplasia. Dermatologica.1970;141:329–34.
32.
CreminBConnorJMBeightonP. The radiological spectrum of fibrodysplasia ossificans progressive. Clin Radiol.1982;33:499–508.
33.
DangelJH. Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders—clinical and echocardiographic changes in 64 patients. Eur J Pediatr.1998;157:534–8.
34.
De SanctisLVaiSAndreoMR. Brachydactyly in 14 genetically characterized pseudohypoparathyroidism type Ia patients. J Clin Endocrinol Metab.2004;89:1650–5.
35.
DreyerSDZhouGBaldiniA. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet.1998;19:47–50.
36.
DunstonJALinSParkJW. Phenotype severity and genetic variation at the disease locus: an investigation of nail dysplasia in the nail patella syndrome. Ann Hum Genet.2005;69:1–8.
37.
EllisRWVan CreveldS: A syndrome characterized by ectodermal dysplasia, polydactyly, chondrodysplasia and congenital morbus cordis. Report of three cases. Arch Dis Child.1940. pp 15–85.
38.
FernandesRKWilkinDJWeisMA. Incorporation of structurally defective type II collagen into cartilage matrix in Kniest chondrodysplasia. Arch Biochem Biophys.1998;355:282–90.
39.
FrancomanoCAOrtez De LunaRIIdeSE. The gene for the Ellis–van Creveld syndrome maps to chromosome 4p16. Am J Hum Genet.1995;57:a191.
40.
FrayhaRMelhernRIdrissH. The Kniest (Swiss cheese cartilage) syndrome. Description of a distinct arthropathy. Arthritis Rheum.1979;22:286–9.
41.
GeschwindCTonkiMA. Carpal tunnel syndrome in children with mucopolysaccharidosis and related disorders. J Hand Surg.1992;17A:44–7.
42.
GiampietroPFPetersonMSchneiderR. Assessment of bone mineral density in adults and children with Marfan syndrome. Osteoporos Int.2003;14:559–63.
43.
GlassRBJTifftCJ. Radiologic changes in infancy in McKusick cartilage hair hypoplasia. Am J Med Genet.1999;86:312–15.
44.
GoltzmanDColeDEC. Hypoparathyroidism. In: FavusMJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 4th ed. Philadelphia: William and Wilkins; 1999. p. 226–30.
45.
GoshenESchwartzAZilkaLRZwanST. Bilateral accessory iliac horns. Pathognomonic findings in nail–patella syndrome. Scintigraphic evidence on bone scan. Clin Nucl Med.2000;25:476–7.
46.
GuideraKJSatterwhiteYOgdenJA. Nail patella syndrome: a review of 44 orthopaedic patients. J Pediatr Orthop.1991;11:737–42.
47.
HallJG. The natural history of achondroplasia. Basic Life Sci.1988;48:3–9.
48.
HalleMACollippPJRoginskyM. Cartilage–hair hypoplasia in childhood. New York J Med.1970;70:2705–8.
49.
HarrisonRJPitcherJDMizelMS. The radiographic morphology of foot deformities in patients with fibrodysplasia ossificans progressiva. Foot Ankle Int.2005;26:937–41.
50.
HermannsPBertuchAABertinTK. Consequences of mutations in the noncoding RMRP RNA in cartilage–hair hypoplasia. Hum Mol Genet.2005;14:3723–40.
51.
HiroseYNakashimaEObashiH. Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage–hair hypoplasia. J Hum Genet.2006;51:706–10.
52.
HortonWA. Recent milestones in achondroplastic research. Am J Med Genet.2006;140A:166–9.
53.
HowardTDGuttmacherAEMcKinnonW. Autosomal dominant postaxial polydactyly, nail dystrophy and dental abnormalities map to chromosome 4p16 in the region containing the Ellis–van Creveld syndrome locus. Am J Hum Genet.1997;61:1405–12.
54.
ItinPHEichGFistarolSK. Missing creases of distal finger joints as a diagnostic clue of nail–patella syndrome. Dermatology.2006;213:153–5.
KaplanFS. Fibrodysplasia ossificans progressiva: a historical perspective. Clin Re Bone Miner Metab.2005;3:178–81.
57.
KaplanFSTabasJAGannonFH. The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J Bone Jt Surg.1993;75A:220–30.
58.
KitohHKitakojiTKuritaK. Deformities of the elbow in achondroplasia. J Bone Jt Surgery.2002;84B:680–3.
59.
KopitsS. Orthopedic complications of dwarfism. Clin Orthop.1976;114:153–79.
60.
KuijpersTWRidanpääMPetersM. Short-limbed dwarfism with bowing, combined immune deficiency and late onset aplastic anaemia caused by novel mutations in the RMPR gene. J Med Genet.2003;40:761–6.
61.
KunzlerAFarmandM. Typical changes in the viscerocranium in acromegaly. J Craniomaxillofac Surg.1991;19:332–40.
62.
LachmanRSRimoinDLHollsterDW. The Kniest syndrome. AJR1975;123:805–14.
63.
LeightonSEPapsinBVellodiA. Disordered breathing during sleep in patients with mucopolysaccharidoses. Int J Pediatr Otrorhinolaryngol.2001;58:127138.
64.
LevineMA. Parathyroid hormone resistance syndromes. In: FavusMJ, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia: William and Wilkins; 1999. p. 230–53.
65.
LiebermanSABjorkengrenAGHoffmanAR. Rheumatologic and skeletal changes in acromegaly. Endocrinol Metab Clin North Am.1992;21:615–31.
66.
LuckyAWTsangR. Clinical vignette: pseudopseudohypoparathyroidism presenting with osteoma cutis. J Bone Miner Res.1997;12:995.
MäkitieOMarttinenEKaitilaI. Skeletal growth in cartilage-hair hypoplasia: a radiological study of 82 patients. Pediatr Radiol.1992;22:434–9.
69.
MaldjianCChewFSKleinR. Kniest dysplasia: new radiographic features in the skeleton. Radiology Case Reports.2007;2:72–7.
70.
MaroteauxPLamyM. Hurler's disease. Morquio's disease and related mucopolysaccharidoses. J Pediat.1965;67:312–23.
71.
MaumeneeIH. The eye in the Marfan syndrome. Trans Am Opthalmol Soc.1981;79:684–733.
72.
MavrodontidisANZalavrasCGPapadonikolakisASoucacosNN. Bilateral absence of the patella in nail-patella syndrome: delayed presentation with anterior knee instability. Arthroscopy.2004;20:e89–93.
73.
McIntoshICloughMVSchafferAA. Fine mapping of the nail-patella syndrome locus at 9q34. Am J Hum Genet.1997;60:133–42.
74.
McKusickVA. Ellis-van Creveld syndrome and the Amish. Nature Genet.2000;24:203–4.
75.
MostafaMITemtamySAEl-GaammalMAMazenIM. Unusual pattern of inheritance and orodental changes in the Ellis-van Creveld syndrome. Genet Couns.2005;16:75–83.
76.
MuenzerJ. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr.2004;144:S27–34.
77.
NeufeldEFMuenzerJ. The mucopolysaccharidoses. In: ScriverCRBeaudetALSlyWS, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, Inc; 2001. p. 3421–52.
78.
PonsetiIV. Skeletal growth in achondroplasia. J Bone Jt Surg.1970;52A:701–16.
79.
RidanpääMSistonenPRockasS. Worldwide mutation spectrum in cartilage–hair hypoplasia: ancient founder origin of the major 70A–>G mutation of the untranslated RMRP. Eur J Hum Genet.2002;10:439–47.
80.
RimoinDLLachmanRS. Genetic disorders of the osseous skeleton. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St Louis: Mosby; 1993. p. 557–689.
81.
RimoinDLLachmanRS. Genetic disorders of the osseous skeleton: Kniest-Stickler dysplasia group. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St. Louis: Mosby; 1993. p. 601–5.
82.
RousseauFBonaventureJLegeai-MalletL. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature.1994;371:252–4.
83.
SartorisDJReznickD. The horn: a pathognomonic feature of paediatric bone dysplasias. Aus Paediatr J.1987;23:347–9.
84.
SatoUKitanakaSSekineT. Functional characterization of LMX1B mutations associated with nail–patella syndrome. Pediatr Res.2005;57:783–8.
85.
SchroederHWZasloffM. The hand and foot malformations in fibrodysplasia ossificans progressiva. Johns Hopkins Medical J.1980;147:73–8.
86.
SeitzCSHammH. Congenital brachydactyly and nail hypoplasia: clue to bone-dependent nail formation. Br J Dermatol.2005;152:1339–42.
87.
SergiCVoightlanderTZoubaaS. Ellis–van Creveld syndrome: a generalized dysplasia of enchondral ossification. Pediatr Radiol.2001;31:289–93.
88.
ShihSLLeeYJLinSP. Airway changes in children with mucopolysaccharidoses. Acta Radiol.2002;43:40–3.
89.
ShoreEMFeldmanGJXuMKaplanFS. The genetics of fibrodysplasia ossificans progessiva. Clin Rev Bone Mineral Metab.2005;3:201–4.
90.
SulisaloTSistonenPHästbackaJ. Cartilage–hair hypoplasia gene assigned to chromosome 9 by linkage analysis. Nat Gent.1993;3:338–41.
91.
Van de VeldeSFillmanRYandowS. Protrusio acetabuli in Marfan syndrome: history, diagnosis and treatment. J Bone Jt Surg.2006;88A:639–46.
92.
WhitelyCB. Mucopolysaccharidosis Type VI. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St. Louis: Mosby; 1993. p. 442–50.
93.
WhitelyCB. Mucopolysaccharidosis Type IV. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St. Louis: Mosby; 1993. p. 431–41.
94.
WhitleyCB. The mucopolysaccharidoses. In: BeightonP, editor. McKusick's heritable disorders of connective tissue. 5th ed. St. Louis: Mosby; 1993. p. 367–499.
95.
WilsonWGAylsworthASFoldsJDWhisnantJK. Cartilage–hair hypoplasia (metaphyseal chondrodysplasia, type McKusick) with combined immune deficiency: variable expression and development of immunologic functions in sibs. Birth Defects Orig Artic Ser.1978;XIV(6A):117–29.
96.
WooCC. Radiological features and diagnosis of acromegaly. J Manipulative Physiol Ther.1988;11:2306–213.
97.
WraithJEAlaniSM. Carpal tunnel syndrome in the mucopolysaccharidoses and relted disorders. Arch Dis Child.1990;65:962–3.
